ISSN: 0378-7966 eISSN: 2107-0180
Subject:
pharmacy and pharmacology
Published by Springer-Verlag 
No Issue Number- A rapid determination of drug candidate tyrosol galactoside in rat plasma by HPLC and its application to the pharmacokinetics study
Abstract A simple and sensitive HPLC method has been developed and validated for the determination of tyrosol galactoside (TG) in rat plasma. After one-step protein precipitation with methanol, plasma samples were separated on an Ultimate AQ–C 18 column (150 mm × 4.6 mm, 5 μm) using acetonitrile–water (7:93, v/v) as mobile phase at a flow rate of 1.2 mL/min. The ultraviolet detection wavelength was set at 275 nm. The lower limit of quantification was 1.140 μg/mL. The calibration curve was linear over a concentration range of 1.140–228.0 μg/mL. The assay accuracy and precision were within the range of 99.6–103.0 and 2.17–6.23%, respectively. The developed method was successfully applied to the pharmacokinetics study of TG in rats after intravenous and oral administration. The bioavailability of TG in rats is 27.9%.
- Content Type Journal Article
- DOI 10.1007/s13318-010-0015-8
- Authors
- Qingwei Wang, Department of Pharmacy, The Second Affiliated Hospital, Fourth Military Medical University, 17 Changlexi Street, Xi’an, 710032 People’s Republic of China
- Yu Wang, Department of Medicinal Chemistry, Fourth Military Medical University, 17 Changlexi Street, Xi’an, 710032 People’s Republic of China
- Yating Deng, Department of Pharmacology, Fourth Military Medical University, Xi’an, 710032 People’s Republic of China
- Tianrao Shi, Department of Medicinal Chemistry, Fourth Military Medical University, 17 Changlexi Street, Xi’an, 710032 People’s Republic of China
- Xueying Liu, Department of Medicinal Chemistry, Fourth Military Medical University, 17 Changlexi Street, Xi’an, 710032 People’s Republic of China
- Xiaoli Sun, Department of Medicinal Chemistry, Fourth Military Medical University, 17 Changlexi Street, Xi’an, 710032 People’s Republic of China
- Xiaoye Li, Department of Medicinal Chemistry, Fourth Military Medical University, 17 Changlexi Street, Xi’an, 710032 People’s Republic of China
- Dan Zhou, Department of Medicinal Chemistry, Fourth Military Medical University, 17 Changlexi Street, Xi’an, 710032 People’s Republic of China
- The effects of an investigational antimalarial agent, NIPRD-AM1 on the single dose pharmacokinetics of metronidazole in healthy human volunteers
Abstract The effect of concurrent administration of a novel phytomedicine, NIPRD-AM1 used for the treatment of malaria on the pharmacokinetics of metronidazole was investigated in healthy volunteers. The study was a completely randomized one, crossover involving administration of single dose metronidazole tablets (200 mg × 2) concomitantly with NIPRD-AM1 capsules (250 mg × 2) to 11 healthy volunteers. Blood samples were collected before and at pre-determined time intervals following administration of the drugs. Serum concentrations of the unchanged metronidazole were analyzed using a modified simple and sensitive reversed phase high performance liquid chromatography (HPLC) method. The method showed good precision for metronidazole with coefficient of variation less than 10%. The Pharmacokinetic parameters (AUC, C max , and T max ) were generated using GraphPad Prism software version 2. The derived pharmacokinetic parameters (AUC, C max ) following the administration of metronidazole alone and co-administration with NIPRD-AM1 were 76.12 μg/ml per hour, 7.94 μg/ml and 73.52 μg/ml per hour, 7.83 μg/ml, respectively. This differences were not statistically significant ( P < 0.05) and the relative bioavailability was found to be about 96%. The comparable relative bioavailabilty value obtained shows that there is little or no interaction between NIPRD-AM1 and metronidazole. The findings, therefore, showed that metronidazole can be administered with the phytomedicine NIPRD-AM1 without any significant effect on the pharmacokinetic profiles of metronidazole.
- Content Type Journal Article
- DOI 10.1007/s13318-010-0012-y
- Authors
- Obiageri O. Obodozie, Department of Medicinal Chemistry and Quality Control, National Institute for Pharmaceutical Research & Development (NIPRD), Idu Industrial Area, P.M.B. 21, Abuja, Nigeria
- Benjamin U. Ebeshi, Department of Medicinal Chemistry and Quality Control, National Institute for Pharmaceutical Research & Development (NIPRD), Idu Industrial Area, P.M.B. 21, Abuja, Nigeria
- Kudirat B. Mustapha, Department of Medicinal Chemistry and Quality Control, National Institute for Pharmaceutical Research & Development (NIPRD), Idu Industrial Area, P.M.B. 21, Abuja, Nigeria
- Rukaiyatu A. Kirim, Department of Medicinal Chemistry and Quality Control, National Institute for Pharmaceutical Research & Development (NIPRD), Idu Industrial Area, P.M.B. 21, Abuja, Nigeria
- Margaret Ekpenyong, NIPRD Staff and Research Clinic, Abuja, Nigeria
- Uford S. Inyang, NIPRD Staff and Research Clinic, Abuja, Nigeria
- Determination of finasteride in human plasma by liquid chromatography–electrospray ionization tandem mass spectrometry with flow rate gradient
Abstract In this study, an attempt was made to describe and validate liquid chromatography–electrospray ionization tandem mass spectrometry as a fast, sensitive and reproducible method for determining finasteride in human plasma. Finasteride and internal standard (pantoprazole) were extracted by liquid–liquid extraction using methyl tert-butyl ether. Separation was performed by using a flow rate gradient on a reverse phase C 18 column at 25°C. The mobile phase consisted of methanol–water (70:30, v/v) containing 0.5% anhydrous formic acid. The protonated analytes were quantitated in positive ionization by multiple reaction monitoring in mass spectrometry. The mass transitions are m/z 373.4→305.3 and 384.1→200.0 for finasteride and pantoprazole, respectively. The method had a run time of 3.6 min and a linear calibration curve at a range of 0.2–100 ng mL −1 ( r 2 = 0.9958). The lower limit of quantification was 0.2 ng mL −1 . The extraction recoveries of finasteride from the biological matrix were more than 82.7%, and the intra- and inter-day precision of the assay at four concentrations were 2.4–8.0% with an accuracy of 94.3–105.8%. The developed method requires less plasma (0.1 mL), but has high sensitivity. The validated method has been successfully used to analyze human plasma samples in pharmacokinetic or bioequivalence studies.
- Content Type Journal Article
- DOI 10.1007/s13318-010-0013-x
- Authors
- Lihua Yuan, School of Pharmacy, Nanjing Medical University, Nanjing, 210029 People’s Republic of China
- Meijuan Ding, School of Pharmacy, Nanjing Medical University, Nanjing, 210029 People’s Republic of China
- Jing Ma, School of Pharmacy, Nanjing Medical University, Nanjing, 210029 People’s Republic of China
- Jinhui Xu, School of Pharmacy, Nanjing Medical University, Nanjing, 210029 People’s Republic of China
- Xiaoli Wu, School of Pharmacy, Nanjing Medical University, Nanjing, 210029 People’s Republic of China
- Jing Feng, Nanjing Xinbai Pharmaceutical, Biological Medicine Science & Technology Park of the Economic and Technological Development Zone, Nanjing, 210038 People’s Republic of China
- Fei Shen, Nanjing Xinbai Pharmaceutical, Biological Medicine Science & Technology Park of the Economic and Technological Development Zone, Nanjing, 210038 People’s Republic of China
- Xuemin Zhou, School of Pharmacy, Nanjing Medical University, Nanjing, 210029 People’s Republic of China
- Pharmacokinetic interaction between zolpidem and ciprofloxacin in healthy volunteers
Abstract Our objective was to evaluate a possible pharmacokinetic interaction between zolpidem and ciprofloxacin in healthy volunteers. The study consisted of two periods: Period 1 (reference), when each volunteer received a single dose of 5 mg zolpidem and Period 2 (test), when each volunteer received a single dose of 5 mg zolpidem and 500 mg ciprofloxacin. Between the two periods, the subjects were treated for 5 days with a single daily dose of 500 mg ciprofloxacin. Plasma concentrations of zolpidem were determined during a 12-hour period following drug administration. Pharmacokinetic parameters of zolpidem administered in each treatment period were calculated using non-compartmental analysis and the data from two periods were compared to determine statistically significant differences. In the two periods of treatments, the mean peak plasma concentrations ( C max ) were 75.73 ± 28.34 ng/ml (zolpidem alone) and 80.58 ± 22.40 ng/ml (zolpidem after pre-treatment with ciprofloxacin). The t max , times taken to reach C max , were 0.91 ± 0.42 and 1.44 ± 0.61 h, respectively, and the total areas under the curve (AUC 0–∞ ) were 300.2 ± 115.5 and 438.1 ± 142.6 ng h/ml, respectively. The half-life of zolpidem was 2.39 ± 0.53 h when administered alone and 3.34 ± 0.87 h after pre-treatment with ciprofloxacin. These differences were statistically significant for C max , t max , AUC 0–∞ , half-life and mean residence time. Ciprofloxacin interacts with zolpidem in healthy volunteers, raising its bioavailability by about 46%. This magnitude of effect is likely to be clinically significant.
- Content Type Journal Article
- DOI 10.1007/s13318-010-0014-9
- Authors
- Laurian Vlase, Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, University of Medicine and Pharmacy “Iuliu Haţieganu”, Emil Isac 13, 400023 Cluj-Napoca, Romania
- Adina Popa, Department of Clinical Pharmacy, Faculty of Pharmacy, University of Medicine and Pharmacy “Iuliu Haţieganu”, Emil Isac 13, 400023 Cluj-Napoca, Romania
- Maria Neag, 1st Medical Clinic, Clinicilor 3-5, 400006 Cluj-Napoca, Romania
- Dana Muntean, Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, University of Medicine and Pharmacy “Iuliu Haţieganu”, Emil Isac 13, 400023 Cluj-Napoca, Romania
- Sorin E. Leucuţa, Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, University of Medicine and Pharmacy “Iuliu Haţieganu”, Emil Isac 13, 400023 Cluj-Napoca, Romania
- Persistence of reserpine in rat brain: gas chromatographic — mass fragmentographic identification and quantitative determination
Summary The highly sensitive and specific combination of a gas chromatographic procedure with mass fragmentographic detection was adopted in order to determine the nanogram concentration of reserpine-like material persisting in rat brain, with more adequate information as to its actual chemical structure. Quantification was achieved by focussing the mass spectrometer upon the ions at m/e 608, the molecular ion and base peak in the spectrum of reserpine; m/e 634, the molecular ion of rescinnamine (internal standard) and m/e 195, a fragment ion common to both reserpine and deserpidine (the latter also used as an internal standard for multiple ion detection). No column adsorption, decomposition or C 3-epimerization was observed during the analyses when trideuterated reserpine was used as a carrier. Satisfactory agreement resulted from the comparison of the data of radioisotopic assays previously performed in our laboratory, with those obtained by the use of the present method.
- Content Type Journal Article
- Pages 25-34
- DOI 10.1007/BF03192276
- Authors
- C. Pantarotto, Laboratory of Mass Spectrometry, USA
- G. Belvedere, Laboratory of Mass Spectrometry, USA
- A. Frigerio, Laboratory of Mass Spectrometry, USA
- T. Mennini, Laboratory of Drug Metabolism, Istituto di Ricerche Farmacologiche «Mario Negri», Via Eritrea, 62, 20157 Milan, Italy
- L. Manara, Laboratory of Drug Metabolism, Istituto di Ricerche Farmacologiche «Mario Negri», Via Eritrea, 62, 20157 Milan, Italy
- New books
<p class="abstract">New books</p><ul>
<li><span class="labelName">Content Type </span><span class="labelValue">Journal Article</span></li><li>Pages 79-82</li><li>DOI 10.1007/BF03192292</li>
</ul><ul class="parents">
<ul class="details">
<li><span class="header labelName">Journal </span><span class="labelValue"><a href="http://www.springerlink.com/content/121759/">European Journal of Drug Metabolism and Pharmacokinetics</a></span></li><li><span class="labelName">Online ISSN </span><span class="labelValue">2107-0180</span></li><li><span class="labelName">Print ISSN </span><span class="labelValue">0378-7966</span></li>
</ul><ul class="details">
<li><span class="header labelName">Journal Volume </span><span class="labelValue">Volume 20</span></li>
</ul><ul class="details">
<li><span class="header labelName">Journal Issue </span><span class="labelValue"><a href="http://www.springerlink.com/content/j9w1m0426962/">Volume 20, Number 1</a></span></li>
</ul>
</ul>
- Events
<p class="abstract">Events</p><ul>
<li><span class="labelName">Content Type </span><span class="labelValue">Journal Article</span></li><li>Pages 83-88</li><li>DOI 10.1007/BF03192293</li>
</ul><ul class="parents">
<ul class="details">
<li><span class="header labelName">Journal </span><span class="labelValue"><a href="http://www.springerlink.com/content/121759/">European Journal of Drug Metabolism and Pharmacokinetics</a></span></li><li><span class="labelName">Online ISSN </span><span class="labelValue">2107-0180</span></li><li><span class="labelName">Print ISSN </span><span class="labelValue">0378-7966</span></li>
</ul><ul class="details">
<li><span class="header labelName">Journal Volume </span><span class="labelValue">Volume 20</span></li>
</ul><ul class="details">
<li><span class="header labelName">Journal Issue </span><span class="labelValue"><a href="http://www.springerlink.com/content/j9w1m0426962/">Volume 20, Number 1</a></span></li>
</ul>
</ul>
- Editorial
<p class="abstract">Editorial</p><ul>
<li><span class="labelName">Content Type </span><span class="labelValue">Journal Article</span></li><li>Pages 1-2</li><li>DOI 10.1007/BF03192282</li><li><span class="labelName">Authors</span><ul>
<li>A. Benakis</li>
</ul></li>
</ul><ul class="parents">
<ul class="details">
<li><span class="header labelName">Journal </span><span class="labelValue"><a href="http://www.springerlink.com/content/121759/">European Journal of Drug Metabolism and Pharmacokinetics</a></span></li><li><span class="labelName">Online ISSN </span><span class="labelValue">2107-0180</span></li><li><span class="labelName">Print ISSN </span><span class="labelValue">0378-7966</span></li>
</ul><ul class="details">
<li><span class="header labelName">Journal Volume </span><span class="labelValue">Volume 20</span></li>
</ul><ul class="details">
<li><span class="header labelName">Journal Issue </span><span class="labelValue"><a href="http://www.springerlink.com/content/j9w1m0426962/">Volume 20, Number 1</a></span></li>
</ul>
</ul>
- Thein vitro metabolism of mebendazole by pig, rat and dog liver fractions
Summary Mebendazole- 14 C was incubated with the 10,000 g and 100,000 g supernatant fractions and the microsomal fractions of pig, rat and dog liver. The metabolism progressed remarkably slowly. The metabolites were separated by extraction and thin-layer chromatography, and characterized by comparative thin-layer chromatography and mass spectrometry. The major metabolite was methyl[5-(α-hydroxy-α-phenylmethyl)-lH-benzimidazol-2-yl]carbamate, resulting from a reduction of the ketone of mebendazole. After 4 hours, this metabolite accounted for 50, 58 and 93 % of the total radioactivity for the pig, rat and dog 10,000 g supernatant fractions respectively. The 100,000 g supernatant fractions as well as the microsomal fractions of the three different species contained reductases able to reduce the ketone of mebendazole. A second metabolite (2-amino-lHyl)phenylmethanone, resulting from a carbamate hydrolysis, was only formed with the 10,000 g supernatant and the microsomal fraction of pig liver (about 5 % after 4 hours); this metabolic pathway was shown to be inhibited by SKF-525 A.
- Content Type Journal Article
- Pages 35-40
- DOI 10.1007/BF03192277
- Authors
- W. E. G. Meuldermans, Research Laboratoria, Dept. of Drug Metabolism Janssen Pharmaceutica n.v., Turnhoutsebaan 30, B-2340 Beerse, Belgium
- R. M. A. Hurkmans, Research Laboratoria, Dept. of Drug Metabolism Janssen Pharmaceutica n.v., Turnhoutsebaan 30, B-2340 Beerse, Belgium
- W. F. J. Lauwers, Research Laboratoria, Dept. of Drug Metabolism Janssen Pharmaceutica n.v., Turnhoutsebaan 30, B-2340 Beerse, Belgium
- J. J. P. Heykants, Research Laboratoria, Dept. of Drug Metabolism Janssen Pharmaceutica n.v., Turnhoutsebaan 30, B-2340 Beerse, Belgium
- Comparison of the pharmacokinetics of phenacetin in beagles after oral or intravenous administration
Summary Six beagles received intravenous and oral doses of 50 mg/kg phenacetin. Plasma concentrations of phenacetin, paracetamol, and p -phenetidin were determined and pharmacokinetic parameters calculated. Phenacetin showed rate constants for absorption and elimination of 0.025 and 0.033 (min −1 ) and an apparent metabolic clearance rate of about 350 ml/min. Paracetamol and p -phenetidin elimination rate constants were 0.02 and 0.015 (min −1 ), respectively. There was no difference in pharmacokinetics or metabolic pattern between both routes of phenacetin administration.
- Content Type Journal Article
- Pages 21-24
- DOI 10.1007/BF03192275
- Authors
- S. Souchay, Pharmakologisches Institut der Universität München, Nussbaumstrasse 26, D-800 München 2, Federal Republick of Germany
- A. Wörner, Pharmakologisches Institut der Universität München, Nussbaumstrasse 26, D-800 München 2, Federal Republick of Germany
- H. G. Kampffmeyer, Pharmakologisches Institut der Universität München, Nussbaumstrasse 26, D-800 München 2, Federal Republick of Germany
- H. K. Selbmann, Institut für Medizinische Informationsverarbeitung, Statistik und Biomathematik der Universitat München, Germany
- Bio-International ’94 Conference on Bioavailability, Bioequivalence and Pharmacokinetic Studiesand Pre-Conference Satellite on ‘in vivo/in vitro correlation’
Bio-International ’94 Conference on Bioavailability, Bioequivalence and Pharmacokinetic Studies and Pre-Conference Satellite on ‘in vivo/in vitro correlation’
- Content Type Journal Article
- Pages 3-13
- DOI 10.1007/BF03192283
- Authors
- H. H. Blume
- I. J. McGilveray
- K. K. Midha
- Pharmacokinetic study of 2,3-dichloro 4-[2-thienyl keto14C] phenoxyacetic acid (Tienilic acid) in animals I. Localisation, distribution and elimination of14C Tienilic acid in animals
Summary The localization, distribution and elimination of 14 C-Tienilic acid, a new diuretic and hypouricemic drug has been described. This study was carried out using 14 C labelled compound on four different animal species: mice, rats, pigs and dogs. The blood level is expressed as /gmg/ml equivalents of the administered product. After oral administration, the absorption rate of this product in doses of 5 mg/kg for rats, pigs and dogs was between 50 and 80 %, depending on the species. Tienilic acid was rapidly distributed in most of the essential organs and tissues with the exception of the brain. In the blood the product was found only at the plasmatic level with high plasmatic protein binding, around 72–95 %. Biliary and particularly urinary elimination was fast and practically complete in 48 hours.
- Content Type Journal Article
- Pages 41-49
- DOI 10.1007/BF03192278
- Authors
- Y. Dormard, Isotope Laboratory, Department of Pharmacokinetics and Metabolism of the Research and Pharmacology Center Albert-Rolland, 4, rue de la Division-Leclerc, 91380 Chilly-Mazarin, France
- J. -C. Levron, Isotope Laboratory, Department of Pharmacokinetics and Metabolism of the Research and Pharmacology Center Albert-Rolland, 4, rue de la Division-Leclerc, 91380 Chilly-Mazarin, France
- P. Adnot, Isotope Laboratory, Department of Pharmacokinetics and Metabolism of the Research and Pharmacology Center Albert-Rolland, 4, rue de la Division-Leclerc, 91380 Chilly-Mazarin, France
- T. Lebedeff, Isotope Laboratory, Department of Pharmacokinetics and Metabolism of the Research and Pharmacology Center Albert-Rolland, 4, rue de la Division-Leclerc, 91380 Chilly-Mazarin, France
- G. Enjoubault, Isotope Laboratory, Department of Pharmacokinetics and Metabolism of the Research and Pharmacology Center Albert-Rolland, 4, rue de la Division-Leclerc, 91380 Chilly-Mazarin, France
- Essential aspects of mass spectrometryEssential Aspects of Mass Spectrometry, by Alberto Frigerio
<p class="abstract">Essential aspects of mass spectrometry<b>Essential Aspects of Mass Spectrometry</b>, by Alberto Frigerio</p><ul>
<li><span class="labelName">Content Type </span><span class="labelValue">Journal Article</span></li><li>Pages 63-63</li><li>DOI 10.1007/BF03192280</li>
</ul><ul class="parents">
<ul class="details">
<li><span class="header labelName">Journal </span><span class="labelValue"><a href="http://www.springerlink.com/content/121759/">European Journal of Drug Metabolism and Pharmacokinetics</a></span></li><li><span class="labelName">Online ISSN </span><span class="labelValue">2107-0180</span></li><li><span class="labelName">Print ISSN </span><span class="labelValue">0378-7966</span></li>
</ul><ul class="details">
<li><span class="header labelName">Journal Volume </span><span class="labelValue">Volume 1</span></li>
</ul><ul class="details">
<li><span class="header labelName">Journal Issue </span><span class="labelValue"><a href="http://www.springerlink.com/content/lx2572l3q123/">Volume 1, Number 1</a></span></li>
</ul>
</ul>
- A new journal ... why'
A new journal ... why?
- Content Type Journal Article
- Pages 3-3
- DOI 10.1007/BF03192269
- Events
<p class="abstract">Events</p><ul>
<li><span class="labelName">Content Type </span><span class="labelValue">Journal Article</span></li><li>Pages 63-64</li><li>DOI 10.1007/BF03192281</li>
</ul><ul class="parents">
<ul class="details">
<li><span class="header labelName">Journal </span><span class="labelValue"><a href="http://www.springerlink.com/content/121759/">European Journal of Drug Metabolism and Pharmacokinetics</a></span></li><li><span class="labelName">Online ISSN </span><span class="labelValue">2107-0180</span></li><li><span class="labelName">Print ISSN </span><span class="labelValue">0378-7966</span></li>
</ul><ul class="details">
<li><span class="header labelName">Journal Volume </span><span class="labelValue">Volume 1</span></li>
</ul><ul class="details">
<li><span class="header labelName">Journal Issue </span><span class="labelValue"><a href="http://www.springerlink.com/content/lx2572l3q123/">Volume 1, Number 1</a></span></li>
</ul>
</ul>
- Les recherches sur le métabolisme et la pharmacocinétique doivent être considérablement amplifiees ...
Les recherches sur le métabolisme et la pharmacocinétique doivent être considérablement amplifiees ...
- Content Type Journal Article
- Pages 6-6
- DOI 10.1007/BF03192271
- Authors
- Localization, distribution, elimination and metabolism of14C-Sulpiride in rats
Summary The localization, distribution, elimination and metabolism of 14 C-Sulpiride administered in doses of 20 mg/kg by i. p. and oral route in rats is described. Whole-body autoradiography and quantification in organs and tissues as a function of time showed that the distribution of radioactivity throughout the body is general with the highest level in the kidineys, pelvis, liver and hypophysis 1 hour after administration. The blood radioactivity level reaches its maximum 5 minutes after i. p. administration with a value of 11 μg/ml, of which 85 % is due to unchanged Sulpiride. At later determinations, the amount drops to 60–65 % of unchanged Sulpiride. In the bile, the maximum radioactivity is measured between 1 and 1 hour 1/2 in either extra-corporal circuit or choledocal fistula. After i. p. administration, urinary elimination is an average of 64 % of the administered dose in 72 hours, of which 70 % to 55 %, depending on the period, is due to unchanged Sulpiride. Fecal elimination after i. p. administration is an average of 26 % of the administered dose in the 72 hours period. Conversely, after oral administration, urinary elimination represents an average of 18 % of the administered dose in 72 hours and fecal elimination represents an average of 74 % for the same period. Aside from the unchanged product, 7 to 8 metabolites were separated and quantified at the plasmatic, urinary and biliary level. Very low amounts of radioactivity were recovered as 14 CO 2 indicating that the labelled position is very stable.
- Content Type Journal Article
- Pages 51-62
- DOI 10.1007/BF03192279
- Authors
- A. Benakis, Laboratory of Drug Metabolism, School of Medicine, University of Geneva, 20, rue de l’École de Médecine, 1211 Geneva 4, Switzerland
- M. -A. Pongis, Laboratory of Drug Metabolism, School of Medicine, University of Geneva, 20, rue de l’École de Médecine, 1211 Geneva 4, Switzerland
- F. Sugnaux, Laboratory of Drug Metabolism, School of Medicine, University of Geneva, 20, rue de l’École de Médecine, 1211 Geneva 4, Switzerland
- B. Glasson, Laboratory of Drug Metabolism, School of Medicine, University of Geneva, 20, rue de l’École de Médecine, 1211 Geneva 4, Switzerland
- H. Jirounek, Laboratory of Drug Metabolism, School of Medicine, University of Geneva, 20, rue de l’École de Médecine, 1211 Geneva 4, Switzerland
- M. Redard, Laboratory of Drug Metabolism, School of Medicine, University of Geneva, 20, rue de l’École de Médecine, 1211 Geneva 4, Switzerland
- J. Vitus, Laboratory of Drug Metabolism, School of Medicine, University of Geneva, 20, rue de l’École de Médecine, 1211 Geneva 4, Switzerland
- The cost benefit ratio of enantiomeric drugs
Summary Several drugs possess a chiral structure, i.e. they contain one or more stereogenic centres in their molecule. While naturally occurring active principles usually contain a single enantiomer, most chiral drugs produced by chemical synthesis are used in the form of racemic mixtures of two or more diastereoisomers. These stereoisomers (including enantiomers) may interact in different ways with biological structures and, therefore, may exhibit widely different pharmacokinetic and pharmacodynamic properties. In the pharmaceutical industry, partly in response to increasing demands raised by regulatory authorities, these considerations justify the current trend to develop the single enantiomer characterized by the most favourable profile of activity (eutomer). The availability of new chemical and analytical technologies facilitates stereoselective synthetic processes and separation of individual enantiomers from racemic mixtures. Any decision to develop a drug as a single enantiomer, however, should be made only after careful evaluation of the cost-benefit ratio, i.e. when the advantages of the eutomer in terms of efficacy and tolerability outweigh the associated increase in production and development costs with respect to the racemic drug. This article takes into consideration synthetic procedures and pharmacological profiles for a number of chiral drugs in therapeutic use (naproxen, labetalol, and warfarin) or selected for clinical development, such as the beta-blocker dilevalol or the mucokinetic agent 3′-hydroxyfarrerol. These examples demonstrate that the kinetic, pharmacological and toxicological properties of individual enantiomers need to be clearly characterized before any decision can be made concerning the development of a chiral drug. The choice of preferentially developing a single enantiomer should be based on careful consideration of production and development costs and actual therapeutic advantages especially in terms of improved safety.
- Content Type Journal Article
- Pages 15-25
- DOI 10.1007/BF03192284
- Authors
- G. Pifferi, Institute of Pharmaceutical Chemistry, University of Milan, Viale Abruzzi 42, 20131 Milano, Italy
- E. Perucca, Clinical Pharmacology Unit, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
- Pharmacon metabolism and action
Pharmacon metabolism and action
- Content Type Journal Article
- Pages 4-5
- DOI 10.1007/BF03192270
- Authors
- E. J. Ariëns, Pharmacological Institute, University of Nijmegen, The Netherlands
- A forum for publication of new results ...
A forum for publication of new results ...
- Content Type Journal Article
- Pages 8-8
- DOI 10.1007/BF03192273
- Authors
- P. G. Waser, Institute of Pharmacology, University of Zürich, Zürich, Switzerland
- Interaction of theophylline and ipriflavone at the cytochrome P450 level
Summary The effect of ipriflavone administered at a dose of 25 mg/kg and 100 mg/kg and coadministered with theophylline was investigated in selective assays of particular P450 isoenzyme activities. Significant changes could be detected in the activities of CYP2E1 and CYP3A in liver microsomes from male Wistar rats treated with ipriflavone. Induction of CYP2E1 was shown by aniline or p -nitrophenol hydroxylation as a result of ipriflavone treatment. Aniline hydroxylation activity of CYP2E1 was induced by theophylline + ipriflavone (100 mg/kg) coadministration as well. It should be noted that theophylline does not cause alteration in CYP2E1 activity. On the other hand, ipriflavone inhibited ethylmorphine and aminopyrine N-demethylation activities catalysed by CYP3A. An additional effect in the inhibition of aminopyrine N-demethylation could be observed in microsomes from theophylline + ipriflavone treated groups. Our results suggest that the decrease in theophylline metabolism and increasing level of serum theophylline of theophylline-treated patient during ipriflavone administration [Takahashi J. et al. (1992): Eur. J. Clin. Pharmacol., 43, 207–208] may be related to CYP3A inhibition by ipriflavone.
- Content Type Journal Article
- Pages 43-47
- DOI 10.1007/BF03192287
- Authors
- K. Monostory, Central Research Institute for Chemistry, Hungarian Academy of Sciences, H-1525, P.O. Box 17, Budapest, Hungary
- L. Vereczkey, Central Research Institute for Chemistry, Hungarian Academy of Sciences, H-1525, P.O. Box 17, Budapest, Hungary
- Apomorphine pharmacokinetics in Parkinsonism after intranasal and subcutaneous application
Summary Apomorphine was administered subcutaneously and intranasally to 7 patients suffering from Parkinsonism with ‘on-off problems. This comparative pharmacokinetic study showed that the two routes of administration are comparable with respect to absorption kinetics. Apomorphine is rapidly absorbed when administered intranasally or subcutaneously with an absorption half life of 8.6 min and 5.8 min, respectively. The high rate of absorption is also reflected by the time for the plasma concentration to peak (t max ) and the lag times. The t max was 23 min for intranasal route and 18 min for the subcutaneous route while the lag times were 2.8 min and 3.9 min, respectively. The bioavailability of intranasal apomorphine compared to the subcutaneous route amounted to 45%. After intranasal and subcutaneous administrations, the elimination half life of apomorphine amounted to 31 min and 27 min, respectively.
- Content Type Journal Article
- Pages 27-33
- DOI 10.1007/BF03192285
- Authors
- E. Sam, Clinical Pharmacy, Katholieke Universiteit Leuven, Herestraat 49, B-3000 Leuven, Belgium
- A. P. Jeanjean, Neurology Department, Université Catholique de Louvain, Brussels, Belgium
- J. M. Maloteaux, Neurology Department, Université Catholique de Louvain, Brussels, Belgium
- N. Verbeke, Clinical Pharmacy, Katholieke Universiteit Leuven, Herestraat 49, B-3000 Leuven, Belgium
- An interdisciplinary approach for metabolic studies ...
<p class="abstract">An interdisciplinary approach for metabolic studies ...</p><ul>
<li><span class="labelName">Content Type </span><span class="labelValue">Journal Article</span></li><li>Pages 7-7</li><li>DOI 10.1007/BF03192272</li><li><span class="labelName">Authors</span><ul>
<li>S. Garattini, Milan, Italy</li>
</ul></li>
</ul><ul class="parents">
<ul class="details">
<li><span class="header labelName">Journal </span><span class="labelValue"><a href="http://www.springerlink.com/content/121759/">European Journal of Drug Metabolism and Pharmacokinetics</a></span></li><li><span class="labelName">Online ISSN </span><span class="labelValue">2107-0180</span></li><li><span class="labelName">Print ISSN </span><span class="labelValue">0378-7966</span></li>
</ul><ul class="details">
<li><span class="header labelName">Journal Volume </span><span class="labelValue">Volume 1</span></li>
</ul><ul class="details">
<li><span class="header labelName">Journal Issue </span><span class="labelValue"><a href="http://www.springerlink.com/content/lx2572l3q123/">Volume 1, Number 1</a></span></li>
</ul>
</ul>
- Effects of antioxidants on drug absorption in in vivo intestinal ischemia/reperfusion
Abstract Ischemia/reperfusion (I/R) injury must be overcome in order to succeed in small intestinal transplantation. Reactive oxygen species (ROS) are generated by I/R, and they induce lipid peroxidation which is one of the causes of mucosal lesion. We previously reported the protection effects of antioxidants to I/R injury in the in vitro study. In the present study, we examined the inhibitive effect of antioxidants on intestinal I/R injury in the in vivo study. Intestinal ischemia was induced in Wistar/ST rats using the spring scale and the surgical suture for 1 h, followed by reperfusion for 1 h. We used 4,5-dihydroxy-1,3-benzene-disulfonic acid (Tiron), astaxanthin (ATX) and epigallocatechin gallate (EGCG) as antioxidants. The inhibitive effects on mucosal lesion, opening of TJ and decrease in protein expression level of P-gp by in vivo intestinal I/R were admitted by three kinds of antioxidant. Tiron and EGCG inhibited P-gp function but ATX did not. Therefore, for the use of P-gp substrate like immunosuppressants after the intestinal transplantation, ATX, which does not inhibit P-gp is considered to be effective for intestinal I/R injury.
- Content Type Journal Article
- DOI 10.1007/s13318-010-0020-y
- Authors
- Yusuke Takizawa, Department of Drug Absorption and Pharmacokinetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392 Japan
- Takuya Kitazato, Department of Drug Absorption and Pharmacokinetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392 Japan
- Hisanao Kishimoto, Department of Drug Absorption and Pharmacokinetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392 Japan
- Mikio Tomita, Department of Drug Absorption and Pharmacokinetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392 Japan
- Masahiro Hayashi, Department of Drug Absorption and Pharmacokinetics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392 Japan
- Stable isotopes in drug metabolism and pharmacokinetics
Summary The current biopharmaceutical applications of stable isotopes are reviewed. The advantages and drawbacks of the techniques based upon these isotopes are also discussed in comparison with those related to radioisotopes.
- Content Type Journal Article
- Pages 9-20
- DOI 10.1007/BF03192274
- Authors
- R. Roncucci, Research Laboratories, ContinentalPharma, Steenweg op Haacht 30, B-1830 Machelen, (Belgium)
- M. -J. Simon, Research Laboratories, ContinentalPharma, Steenweg op Haacht 30, B-1830 Machelen, (Belgium)
- G. Jacques, Research Laboratories, ContinentalPharma, Steenweg op Haacht 30, B-1830 Machelen, (Belgium)
- G. Lambelin, Research Laboratories, ContinentalPharma, Steenweg op Haacht 30, B-1830 Machelen, (Belgium)
- Metabolism of levomepromazine in man
Summary The phenothiazine drug, levomepromazine (LM), is used in the treatment of psychiatric disorders and as an analgesic. A single 50 or 100 mg dose of LM was given to healthy male volunteers, and urine samples were collected for 24 h. The urine was treated with β-glucuronidase, purified by solid-phase extraction, and analyzed on a GC-MS system for identification of LM metabolites. Mass spectra suggesting 14 different LM metabolites were obtained from the samples. Out of these, 13 spectra could be ascribed to specific metabolites, 5 of which have not previously been identified. All these 5 metabolites were hydroxylated at the phenothiazine nucleus. Although the applied method did not determine the positions of hydroxyl groups on phenothiazine nuclei, 3 of the 5 metabolites were identified as O-desmethyl 3-hydroxy LM, O-desmethyl 7-hydroxy LM, and N,O-didesmethyl 7-hydroxy LM, based on their chromatographic properties. In addition two metabolites, one being hydroxylated on the phenothiazine nucleus, and one being O-demethylated and hydroxylated on the nucleus, were found. It is suggested that these were 8-hydroxy LM and O-desmethyl 8-hydroxy LM. The concentrations of 3-hydroxy LM (free+conjugated) appeared to be much higher than the concentrations of any other metabolite in the samples.
- Content Type Journal Article
- Pages 61-71
- DOI 10.1007/BF03192290
- Authors
- P. -A. Hals, Department of Pharmacology, Institute of Medical Biology, University of Tromsø, Tromsø, Norway
- S. G. Dahl, Department of Pharmacology, Institute of Medical Biology, University of Tromsø, Tromsø, Norway
- The identification and characterisation of chloramphenicol-aldehyde, a new human metabolite of chloramphenicol
Summary The toxic aldehyde derivative of chloramphenicol has previously been reported as a metabolic product only in the rat. Chloramphenicol-aldehyde has been synthesised and characterised and shown to exist in at least two forms, possibly due to rearrangement within the molecule. The authenticated compound has been used to identify chloramphenicol-aldehyde as a metabolic product excreted in the urine of children treated with chloramphenicol.
- Content Type Journal Article
- Pages 35-42
- DOI 10.1007/BF03192286
- Authors
- D. E. Holt, The Karim Centre for Meningitis Research, RPMS Institute of Obstetrics & Gynaecology, Queen Charlotte’s and Chelsea Hospital, Goldhawk Road, W6 0XG London, UK
- In vivo and in vitro kinetics of mofarotene in mouse, rat, dog and man
Summary The pharmacokinetics of mofarotene were investigated in mice, rats and dogs following single intravenous and oral administrations. Healthy volunteers were also given a single oral dose of 300 mg mofarotene. The data indicate a similar disposition for mofarotene in all species studied: low clearance consistent with a high bioavailability following oral dosing, and large volume of distribution indicating an extensive tissue uptake. Also in vitro in liver microsomes, the values for intrinsic clearance were in all species within a 2-fold range. The dog, however, tended to exhibit, both in vitro and in vivo, the lowest clearance. Although (due to the lack of protein binding data) a direct prediction of the in vivo clearance from in vitro data was not possible, the experiments with liver microsomes did provide a clear insight into the rate of elimination of mofarotene in vivo in the different species studied including man.
- Content Type Journal Article
- Pages 49-53
- DOI 10.1007/BF03192288
- Authors
- B. Vallès, F. Hoffmann-La Roche AG, Pharma Division, Preclinical Research, 4002 Basle, Switzerland
- B. Ba, F. Hoffmann-La Roche AG, Pharma Division, Preclinical Research, 4002 Basle, Switzerland
- R. Wyss, F. Hoffmann-La Roche AG, Pharma Division, Preclinical Research, 4002 Basle, Switzerland
- B. Reigner, F. Hoffmann-La Roche AG, Pharma Division, Preclinical Research, 4002 Basle, Switzerland
- Ph Coassolo, F. Hoffmann-La Roche AG, Pharma Division, Preclinical Research, 4002 Basle, Switzerland
- Danggui (Angelica sinensis) affects the pharmacodynamics but not the pharmacokinetics of warfarin in rabbits
Summary Danggui is a popular traditional Chinese medicinal (TCM) herb which is easily obtained by the public. The effects of Danggui on the pharmacokinetics and pharmacodynamics of warfarin were studied in rabbits. Single subcutaneous doses (2 mg/kg) of warfarin were administered to 6 rabbits with or without 3 days treatment with oral Danggui extracts (2 g/kg twice daily). Plasma warfarin concentrations were measured by high performance liquid chromatography (HPLC) for 72 h after each of the two warfarin doses. The prothrombin time (PT) was measured daily for 3 days both during the Danggui treatment period and after warfarin doses. Danggui treatment did not affect PT on its own, but significantly lowered PT values 3 days after co-treatment with single dose warfarin. No significant variations in the single dose pharmacokinetic parameters of warfarin were observed after Danggui treatment. A separate group of 6 rabbits were given daily subcutaneous doses of warfarin (0.6 mg/kg) to achieve steady state level, followed by 3 day treatment with oral Danggui extract (2 g/kg twice daily). The slight increase in PT was not significant and two rabbits died after day 7 of the treatment period. However, there was no significant difference in steady state concentrations of warfarin after the Danggui treatment. Results indicate that precautionary advice should be given to patients who self-medicate with Danggui or other TCM products while on chronic treatment with warfarin.
- Content Type Journal Article
- Pages 55-60
- DOI 10.1007/BF03192289
- Authors
- A. C. T. Lo, Department of Pharmacology, The Chinese University of Hong Kong, Shatin, Hong Kong
- K. Chan, Department of Pharmacology, The Chinese University of Hong Kong, Shatin, Hong Kong
- J. H. K. Yeung, Department of Pharmacology, The Chinese University of Hong Kong, Shatin, Hong Kong
- K. S. Woo, Department of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong
- Improved bioavailability of orally administered andrographolide from pH-sensitive nanoparticles
Abstract Andrographolide, a major bioactive phytoconstituent derived from Androgaphis paniculata that is safe and beneficial in several ailments, was formulated into pH-sensitive nanoparticle suspension with a view of improving its oral bioavailability. The andrographolide-loaded pH-sensitive nanoparticles were prepared by nanoprecipitation technique using Eudragit ® EPO (cationic poly methacrylate copolymer). The 3 2 factorial design was used to optimize the amount of polymer and stabilizer (Pluronic ® F-68). The optimized batch obtained using 0.45% w/v of Eudragit ® EPO and 0.6% w/v of Pluronic ® F-68 showed high-encapsulation efficiency of 93.8 ± 0.67% with particle size of 255 ± 9 nm and zeta potential of 29.3 ± 3.4 mV. The bioavailability of andrographolide from optimized nanoparticles and pure andrographolide was assessed in male Wistar albino rats at a dose of 10 mg/kg. As compared to the pure andrographolide, almost 2.2 and 3.2-fold increase in AUC 0–∞ , C max and 121.53% increase in relative bioavailability were observed for andrographolide from pH-sensitive nanoparticles ( P < 0.05). Shorter T max by about fourfold difference were observed with 2.2-fold decrease in Cl /F. The improved dissolution rate owing to its reduced particle size, increased surface area and reduced diffusion layer thickness may have contributed to oral bioavailability. The results clearly indicate the potential of pH-sensitive nanoparticles for oral delivery of low-bioavailability phytoconstituents such as andrographolide.
- Content Type Journal Article
- DOI 10.1007/s13318-010-0016-7
- Authors
- Bothiraja Chellampillai, Department of Pharmaceutics, Poona College of Pharmacy, Bharati Vidyapeeth University, Erandwane, Pune, Maharashtra 411038, India
- Atmaram Pandurang Pawar, Department of Pharmaceutics, Poona College of Pharmacy, Bharati Vidyapeeth University, Erandwane, Pune, Maharashtra 411038, India
- Expression of UDP-glucuronosyltransferase 1A4 in human placenta at term
Abstract The placenta contains a large variety of metabolizing enzymes, among them UDP-glucuronosyltransferase (UGT). Several UGT2B isozymes have so far been detected in human placenta, but little is known on placental expression of UGT1A isozymes. The antiepileptic drug lamotrigine (LTG) is a UGT1A4-substrate, and its serum concentration falls by over 50% during pregnancy, leading to impaired seizure control. The placenta may be involved in this. Microsomes from term placentas of 4 LTG-users and 10 healthy control subjects were prepared. Western blot analysis detected UGT1A proteins in all placentas. The presence of UGT1A4 in placenta from LTG users was confirmed with UGT1A4 commercial standard and a specific UGT1A4 primary antibody. Since LTG is primarily metabolized by UGT1A4 and this isozyme is shown to be present in placenta at term, it may be hypothesized that the placenta is involved in the fall of LTG serum concentrations during pregnancy.
- Content Type Journal Article
- DOI 10.1007/s13318-010-0021-x
- Authors
- Arne Reimers, Department of Clinical Pharmacology, St. Olavs University Hospital, P. O. Box 3250 Sluppen, 7006 Trondheim, Norway
- Lene Østby, Sør-Trøndelag University College, Faculty of Technology, 7004 Trondheim, Norway
- Ina Stuen, Sør-Trøndelag University College, Faculty of Technology, 7004 Trondheim, Norway
- Eirik Sundby, Sør-Trøndelag University College, Faculty of Technology, 7004 Trondheim, Norway
- Pharmacokinetics and safety of a new bioengineered thrombolytic agent, human tissue urokinase type plasminogen activator in Chinese healthy volunteers
Abstract The aim of our study was to investigate the pharmacokinetics and safety of human tissue urokinase type plasminogen activator (HTUPA) in healthy Chinese subjects after intravenous administration. Thirty-two subjects were given intravenous injection doses of 5–35 mg of HTUPA for safety evaluation. Twenty-four subjects were given 10, 20 or 30 mg HTUPA for pharmacokinetic assessment. Safety and tolerance were evaluated by monitoring adverse events, laboratory parameters, electrocardiography and vital signs. HTUPA concentration in human serum samples was determined by an enzyme-linked immunosorbent assay (ELISA) method. The main pharmacokinetic parameters were calculated by DAS software. HTUPA was generally well tolerated and in the whole study course no serious adverse events occurred. The main pharmacokinetic parameters were as follows: geometric mean [95% confidence interval, CI] for t 1/2 were 1.5 (1.4, 1.6), 1.3 (1.2, 1.4), and 1.2 (1.2, 1.3) h, AUC 0- t were 1.0 (0.7, 1.3), 2.1 (1.5, 2.7), and 5.6 (4.7, 6.6) mg h L −1 , AUC 0–∞ were 1.1 (0.8, 1.3), 2.1 (1.5, 2.7), and 5.8 (4.7, 6.7) mg h L −1 for 10, 20, and 30 mg group, respectively. The main pharmacokinetic parameters were not significantly different between males and females ( P > 0.05). No serious adverse events were reported by the subjects or revealed by clinical or laboratory examinations, suggesting the given doses were safe and well tolerated.
- Content Type Journal Article
- DOI 10.1007/s13318-010-0019-4
- Authors
- Yu-guang Liang, Department of Pharmacology, Affiliated Hospital of Academy of Military Medical Sciences, 8 Dongda Street, Fengtai District, Beijing, 100071 China
- Peng Liu, Department of Emergency Medicine, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853 China
- Hong-zhi Gao, Department of Pharmacology, Affiliated Hospital of Academy of Military Medical Sciences, 8 Dongda Street, Fengtai District, Beijing, 100071 China
- Hai-yan Li, Department of Pharmacology, Affiliated Hospital of Academy of Military Medical Sciences, 8 Dongda Street, Fengtai District, Beijing, 100071 China
- Guang-tao Hao, Department of Pharmacology, Affiliated Hospital of Academy of Military Medical Sciences, 8 Dongda Street, Fengtai District, Beijing, 100071 China
- Xiao-fang Wang, Department of Pharmacology, Affiliated Hospital of Academy of Military Medical Sciences, 8 Dongda Street, Fengtai District, Beijing, 100071 China
- Xi-gang Zhang, Department of Emergency, Affiliated Hospital of Academy of Military Medical Sciences, 8 Dongda Street, Fengtai District, Beijing, 100071 China
- Qing-yi Meng, Department of Emergency Medicine, Chinese PLA General Hospital, 28 Fuxing Road, Beijing, 100853 China
- Ze-yuan Liu, Department of Pharmacology, Affiliated Hospital of Academy of Military Medical Sciences, 8 Dongda Street, Fengtai District, Beijing, 100071 China
- Quantification of pantoprazole in human plasma using LC-MS/MS for pharmacokinetics and bioequivalence study
Abstract A highly sensitive and rapid method for the analysis of pantoprazole in human plasma using liquid chromatography coupled to tandem electrospray ionization mass spectrometry was developed. The procedure involves a simple protein precipitation method with methyl alcohol and separation by RP-HPLC. Detection was performed by positive ion electrospray ionization in multiple reaction monitoring mode, monitoring the transitions m / z 384.1 → 200.0 and m / z 346.1 → 198.0, for quantification of pantoprazole and IS, respectively. The standard calibration curves showed good linearity within the range of 5–5,000 ng mL −1 . The lower limit of quantitation (LLOQ) was about 5 ng mL −1 . The extractive recovery of pantoprazole from the biological matrix was more than 77.58% and the matrix effect was complied with relevant provision. The intra-day accuracy of the drug containing serum samples was more than 92.19% with a precision of 0.79–5.36%. The inter-day accuracy was 85.49% or more, with a precision of 0.91–12.67%. Intra and inter-day accuracy of the assay at four concentrations were 97.9–98.2% with a precision of 4.2–13.9%. This method offered good precision and accuracy and was successfully applied to the pharmacokinetic and bioequivalence studies of 40 mg of enteric-coated pantoprazole in 20 healthy Chinese volunteers.
- Content Type Journal Article
- DOI 10.1007/s13318-010-0018-5
- Authors
- Yun Li, School of Pharmacy, Nanjing Medical University, Nanjing, 210029 People’s Republic of China
- Mei-Juan Ding, School of Pharmacy, Nanjing Medical University, Nanjing, 210029 People’s Republic of China
- Jing Ma, School of Pharmacy, Nanjing Medical University, Nanjing, 210029 People’s Republic of China
- Shu Wang, School of Pharmacy, Nanjing Medical University, Nanjing, 210029 People’s Republic of China
- Xiao-Li Wu, School of Pharmacy, Nanjing Medical University, Nanjing, 210029 People’s Republic of China
- Hui-Juan Xu, Kang Enbei Pharmaceutical Co., Ltd., Hangzhou, 310052 People’s Republic of China
- Zheng-Yu Lu, Kang Enbei Pharmaceutical Co., Ltd., Hangzhou, 310052 People’s Republic of China
- Jian-Jun Zou, Nanjing First Hospital, Nanjing, 210006 People’s Republic of China
- Hong-Wei Fan, Nanjing First Hospital, Nanjing, 210006 People’s Republic of China
- Xue-Min Zhou, School of Pharmacy, Nanjing Medical University, Nanjing, 210029 People’s Republic of China
- Plasma pharmacokinetics and tissue distribution of bufotalin in mice following single-bolus injection and constant-rate infusion of bufotalin solution
Abstract Bufotalin is one of the active antitumor components in Ch’an Su which is a widely used traditional Chinese medicine. However, there is insufficient information on the biopharmaceutical properties of bufotalin based on pharmacokinetic studies. To investigate the pharmacokinetics and tissue distribution of bufotalin, single-bolus injection and constant-rate infusion of bufotalin solution were performed in mice. After single intravenous administration, bufotalin was quickly distributed and eliminated from the plasma with a t 1/2 of 28.6 min and an MRT of 14.7 min. Bufotalin concentrations in brain and lung were significantly higher than those in blood and other tissues at 30 min after dosing. The steady-state bufotalin plasma concentration and tissue distribution were determined using a novel constant-rate infusion device, and the distribution characteristics were similar to those of single-bolus injection. These results indicated that bufotalin could cross the blood–brain barrier and naturally target the lung. Bufotalin might be a promising antitumor candidate for lung cancer.
- Content Type Journal Article
- DOI 10.1007/s13318-010-0017-6
- Authors
- Chui-liang Yu, Shanghai Institute of Pharmaceutical Industry, National Pharmaceutical Engineering and Research Center, Shanghai, 201203 People’s Republic of China
- Hui-min Hou, Shanghai Institute of Pharmaceutical Industry, National Pharmaceutical Engineering and Research Center, Shanghai, 201203 People’s Republic of China
- Effect of sulfated xylans during the interaction of [125I]-thrombin with antithrombin III or heparin cofactor II of human plasma
Summary [ 125 I]-Labeled thrombin was incubated with human plasma and its interactions with the two plasma protease inhibitors antithrombin III (AT-III) or heparin cofactor II (HC-II) were investigated in the presence of oat spelts xylan sulfate (OSXS), sodium pentosan polysulfate (SP-54), and the results were compared with heparin and dermatan sulfate. Addition of OSXS or SP-54 enhanced the complexation of thrombin with HC-II or with both AT-III and HC-II depending upon the concentration and the duration of the interactions of the sulfated compounds with plasma. During the 30 s interaction, OSXS and SP-54 enhanced both AT-III-thrombin and HC-II-thrombin interaction while heparin was more selective and enhanced only the AT-III-thrombin interaction. However after a 2 min interaction, heparin showed an increase in the HC-II-thrombin interaction at higher concentrations. The complexations of AT-III-thrombin and HC-II-thrombin were reversed in the presence of 200 μg/ml of SP-54 during a 30 s interaction or in presence of 100 μg/ml of OSXS during a 2 min interaction. The Western blotting method of detecting thrombin showed that during the 10 s interaction, heparin enhanced the thrombin-AT-III complex formation while OSXS enhanced the thrombin-HC-II complex formation.
- Content Type Journal Article
- Pages 73-77
- DOI 10.1007/BF03192291
- Authors
- R. B. Simmons, Chemistry Department and Cooperative Agriculture Research Center, Prairie View A&M University, 77446 Prairie View, Texas USA
- G. R. Newton, Chemistry Department and Cooperative Agriculture Research Center, Prairie View A&M University, 77446 Prairie View, Texas USA
- V. M. Doctor, Chemistry Department and Cooperative Agriculture Research Center, Prairie View A&M University, 77446 Prairie View, Texas USA
- Pharmacokinetics of [125I]-recombinant human interleukin-11: 1. Absorption, distribution and excretion after subcutaneous administration to male rats
Summary Absorption, distribution, metabolism and excretion of [ 125 I]-rhIL-11 (recombinant human interleukin-11) after subcutaneous administration in rats were investigated. After a single administration, the concentration of radioactivity in the tissues was 2–6-fold higher in the liver and kidneys, and slightly higher in the gastrointestinal tract as compared to the plasma concentration. However, since the concentration in the other tissues was lower than the plasma concentration, the transport of rhIL-11 into tissues appeared to be low. Tissue radioactivity rapidly diminished, thus accumulation of rhIL-11 in tissues was thought to be low. Excretion of radioactivity into urine and feces was almost complete 72 h after administration, with 88.5% of the dosed radioactivity being found in urine and 7.9% in feces. When [ 125 I]-rhIL-11 was administered to bile-duct cannulated rats, 44.4% of the dosed radioactivity was excreted into bile up to 48 h after administration. Most radioactivity in bile and urine was found in the TCA supernatant and low molecular weight fraction by HPLC analysis, indicating that rhIL-11 was eliminated from the body by metabolism.
- Content Type Journal Article
- Pages 403-410
- DOI 10.1007/BF03192301
- Authors
- T. Uchida, Drug Metabolism Laboratories, Yamanouchi Pharmaceutical Co. Ltd, 1-8, Azusawa 1-chome, Itabashi-ku, 174-8511 Tokyo, Japan
- K. Aoyama, Drug Metabolism Laboratories, Yamanouchi Pharmaceutical Co. Ltd, 1-8, Azusawa 1-chome, Itabashi-ku, 174-8511 Tokyo, Japan
- K. Mori, Drug Metabolism Laboratories, Yamanouchi Pharmaceutical Co. Ltd, 1-8, Azusawa 1-chome, Itabashi-ku, 174-8511 Tokyo, Japan
- T. Usui, Drug Metabolism Laboratories, Yamanouchi Pharmaceutical Co. Ltd, 1-8, Azusawa 1-chome, Itabashi-ku, 174-8511 Tokyo, Japan
- T. Watanabe, Drug Metabolism Laboratories, Yamanouchi Pharmaceutical Co. Ltd, 1-8, Azusawa 1-chome, Itabashi-ku, 174-8511 Tokyo, Japan
- Y. Takariki, Tsukuba Laboratory, Life Science Laboratory, Nemoto & Co., Ltd, Mitsukaido, Ibaraki, Japan
- N. Asahara, Tsukuba Laboratory, Life Science Laboratory, Nemoto & Co., Ltd, Mitsukaido, Ibaraki, Japan
- M. Hirose, Tsukuba Laboratory, Life Science Laboratory, Nemoto & Co., Ltd, Mitsukaido, Ibaraki, Japan
- T. Kimura, Tsukuba Laboratory, Life Science Laboratory, Nemoto & Co., Ltd, Mitsukaido, Ibaraki, Japan
- M. Tateishi, Tsukuba Laboratory, Life Science Laboratory, Nemoto & Co., Ltd, Mitsukaido, Ibaraki, Japan
- S. Higuchi, Drug Metabolism Laboratories, Yamanouchi Pharmaceutical Co. Ltd, 1-8, Azusawa 1-chome, Itabashi-ku, 174-8511 Tokyo, Japan
- Pharmacokinetics of progesterone in postmenopausal women
Summary Progesterone was administered percutaneously to postmenopausal women in topical applications on the breast and chest areas in a hydrophilic (gel), lipophilic and an emulsion type base. Venous blood samples were taken 2, 4, 6, 24, 48 and 72 h following administration. The plasma levels were evaluated by radioimmunoassay. Time of maximum concentration (t max ) was, in all cases, in the neighborhood of 4 h. Mean peak plasma concentrations were: 1 ng/ml for the lipophilic, 1.24 ng/ml for the hydrophilic and 2.26 ng/ml for the emulsion type base. The areas under the curves (AUCs) were practically equivalent for the first two methods, but higher values were obtained for administration in the emulsion type base. The elimination was slow, with a half-time varying in the range of 30–40 h for all three types of base, a value that was much higher than those obtained after administration of progesterone via vaginal suppositories. The AUCs were parallel with the peak plasma concentrations: almost 2-fold higher for emulsion than for the gel and lipophilic base. Fit for plasma levels using mono-, bi- and tricompartmental models furnished acceptable results only in the case of monocompartmental model, which raises a number of physiological and physico-chemical considerations. A ‘pseudomonocompartmental’ model was constructed to explain this ‘anomaly’.
- Content Type Journal Article
- Pages 397-402
- DOI 10.1007/BF03192300
- Authors
- C. Mircioiu, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Str. Traian Vuia 6, Bucharest, Romania
- A. Perju, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Str. Traian Vuia 6, Bucharest, Romania
- E. Griu, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Str. Traian Vuia 6, Bucharest, Romania
- G. Calin, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Str. Traian Vuia 6, Bucharest, Romania
- A. Neagu, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Str. Traian Vuia 6, Bucharest, Romania
- D. Enachescu, Faculty of Mathematics, University of Bucharest, Bucharest, Romania
- D. S. Miron, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Str. Traian Vuia 6, Bucharest, Romania
- Pharmacokinetics of progesterone in postmenopausal women:
Summary Progesterone was administered to postmenopausal women in a form of vaginal suppositories containing 100 and 200 mg active substance in Butyrum cacao (BC) and Massa estarinum (ME), a base with emulsifying properties. In the case of single doses, blood samples were taken at 2, 4, 6, 24, 48 and 72 h. Another group of patients received vaginal suppositories (100 mg progesterone) once a day for a 6 day period, with blood samples taken 12 h after each administration. The plasma levels of progesterone were evaluated by radioimmunoassay. The time of maximum concentration (t max ) was 4 h in most cases, and 6 h in the others. The plasma levels were not dose-proportional. Peak plasma concentrations were in the range of 10–15 ng/ml with a mean of 10.5 ng/ml for the 100 mg and 12 ng/ml for the 200 mg doses. The ratio of the mean area under the curve (AUC) for 200 mg and the mean AUC for the 100 mg dose was found to be 1.37. Replacing BC with ME resulted in the lowering of c max and AUC, and an increase in t max following a reducing in the rate and extent of adsorption. In the case of ME suppositories, the variability in AUC, c max and t max was greater compared to that observed with the BC suppositories. Elimination half-time was in the range of 9–10 h for BC and 14 h for ME suppositories. In vitro assessment of the release kinetics from a hydrophobic and an emulsion type base confirmed previous findings: the latter base assured better pharmaceutical availability. The repeated doses did not seem to produce an accumulation of progesterone in the plasma. On the contrary, a small decrease in plasma levels over time appeared during the 6 day period. Numerical analysis revealed an excellent goodness of fit for the in vivo experimental data via biexponential curves, i.e. a pseudomonocompartmental model.
- Content Type Journal Article
- Pages 391-396
- DOI 10.1007/BF03192299
- Authors
- C. Mircioiu, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Str. Traian Vuia 6, Bucharest, Romania
- A. Perju, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Str. Traian Vuia 6, Bucharest, Romania
- A. Neagu, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Str. Traian Vuia 6, Bucharest, Romania
- E. Griu, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Str. Traian Vuia 6, Bucharest, Romania
- G. Calin, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Str. Traian Vuia 6, Bucharest, Romania
- D. S. Miron, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Str. Traian Vuia 6, Bucharest, Romania
- Assessment of blood level with controlled-release dosage forms: Effect of the rate constant of elimination of the drug
Summary Prediction of the drug level in the volume of distribution was made using a numerical model taking into account the following facts: the kinetics of drug release out of the dosage form along the gastrointestinal tract, the kinetics of absorption in the blood compartment and the kinetics of elimination. Various parameters intervene significantly for a given dosage form. Some emphasis was placed upon the rate of elimination of the drug which appears to be the main characteristic for the drug, especially when it is delivered through controlled release dosage forms. The rate of release of the drug out of the dosage form, as well as the dose frequency and the gastrointestinal transit time were also considered. The drug level in the plasma was expressed by the amount of drug as a fraction of the amount of drug initially located in the dosage form.
- Content Type Journal Article
- Pages 383-389
- DOI 10.1007/BF03192298
- Authors
- A. Aïnaoui, Laboratory of Materials and Chemical Engineering, Faculty of Sciences, University of St-Etienne, 23 Dr Paul Michelon, 42023 France
- J. M. Vergnaud, Laboratory of Materials and Chemical Engineering, Faculty of Sciences, University of St-Etienne, 23 Dr Paul Michelon, 42023 France
- Pharmacokinetics of tacrolimus (FK506) in paediatric liver transplant recipients
Summary The pharmacokinetics of intravenous and oral tacrolimus was assessed in paediatric liver transplant patients at two centers in Europe. Sixteen patients, age 0.7 to 13 years, participated in the study; 12 patients were evaluable for intravenous pharmacokinetics, and 16 for oral. Intravenous tacrolimus was given as a continuous 24 h infusion (mean 0.037±0.013 mg/kg/day), and oral tacrolimus was given in 2 doses per day (mean 0.152±0.015 mg/kg). Whole blood samples for the intravenous pharmacokinetic profile were taken before initiation of the first infusion, 4, 8, 12 and 24 h post-infusion, and every 24 h thereafter until intravenous administration was discontinued. During the 12 h wash-out period between intravenous and oral administration, samples were taken every 3 h. Samples for the oral pharmacokinetic profile were taken immediately before the first oral dose and 0.5, 0.75, 1, 2, 2.5, 3, 4, 6, 8, 10 and 12 h post-administration. Non-compartmental procedures were used to characterise the pharmacokinetic parameters. Mean estimates for clearance and terminal half-life were 2.3±1.2 ml/min/kg and 11.5±3.8 h, respectively, following intravenous tacrolimus. The mean bioavailability of oral tacrolimus was 25±20%. A strong correlation was observed between AUC and trough whole blood levels of tacrolimus ( r =0.90). The clearance was approximately 2-fold higher than that previously observed in adults; this could explain the higher dosage requirements in children.
- Content Type Journal Article
- Pages 367-370
- DOI 10.1007/BF03192295
- Authors
- P. E. Wallemacq, Service de Chirurgie Pediatrique, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium
- V. Furlan, Service d’Hepatologie, Hôpital Kremlin-Bicêtre, Paris, France
- A. Möller, Department of Pharmacokinetics, Fujisawa GmbH, PO Box 800628, D-81606 Munich, Germany
- A. Schäfer, Department of Pharmacokinetics, Fujisawa GmbH, PO Box 800628, D-81606 Munich, Germany
- P. Stadler, Department of Pharmacokinetics, Fujisawa GmbH, PO Box 800628, D-81606 Munich, Germany
- I. Firdaous, Service de Chirurgie Pediatrique, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium
- A -M. Taburet, Service d’Hepatologie, Hôpital Kremlin-Bicêtre, Paris, France
- R. Reding, Service de Chirurgie Pediatrique, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium
- S. Clement De Clety, Service de Chirurgie Pediatrique, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium
- J. De Ville De Goyet, Service de Chirurgie Pediatrique, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium
- E. Sokal, Service de Chirurgie Pediatrique, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium
- L. Lykavieris, Service de Chirurgie Pediatrique, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium
- V. Van Leeuw, Service de Chirurgie Pediatrique, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium
- O. Bernard, Service d’Hepatologie, Hôpital Kremlin-Bicêtre, Paris, France
- J. B. Otte, Service de Chirurgie Pediatrique, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium
- N. A. Undre, Department of Pharmacokinetics, Fujisawa GmbH, PO Box 800628, D-81606 Munich, Germany
- Comparative bioavailability of two immediate release tablets of cisapride in healthy volunteers
Summary Relative bioavailability of cisapride was investigated after oral administration of a test versus a reference formulation of immediate release tablets of cisapride, both with 10 mg per unit. The study was conducted in a two-way cross-over design, as a single dose open-label randomised trial. The two formulations were administered in two treatment days, separated by a washout period of 6 days, in fasted subjects who received one single oral dose of 20 mg of one study medication of cisapride as two 10 mg tables. Multiple samples were collected over 24 h post-dosing. Plasma samples were assayed for cisapride using a selective and sensitive high-performance liquid chromatography (HPLC) method with UV detection. The pharmacokinetic parameter values (mean±RSD%) of cisapride as the test formulation were: AUC 0−∞ =329±20.9 ng.h/ml, C max =52.8±22.6 ng/ml, t max =1.26±22.0 h and t 1/2 =4.08 \+-15 h. Following administration of the reference formulation the values obtained for the same parameters were: AUC 0\t-\t8 =317\+-19.2 ng.h/ml, C max =49.2\+-21.3 ng/ml, t max =1.38\+-30.1 h and t 1/2 =4.52\+-24.8 h. These results show that the two cisapride formulations can be considered as bioequivalent, with respect to the above mentioned parameters.
- Content Type Journal Article
- Pages 377-381
- DOI 10.1007/BF03192297
- Authors
- M. T. Maya, Centro de Patogenese Molecular, Faculdade de Farmácia da Universidade de Lisboa, Av. Forças Armadas, 1600 Portugal
- C. R. Domingos, Faculdade de Farmácia da Universidade de Lisboa, Portugal
- M. T. Guerreiro, Faculdade de Farmácia da Universidade de Lisboa, Portugal
- A. P. Filipe, Tecnimede SA, Portugal
- J. A. Morais, Faculdade de Farmácia da Universidade de Lisboa, Portugal
- The effect of stress on the pharmacokinetics and pharmacodynamics of glibenclamide in diabetic rats
Summary Optimal management of the diabetic patient includes normalization of glucose concentration. Attainment of this goal is difficult because stress has long been shown to have a major effect on metabolic activity. The aim of this study was to assess the effect of stress on the pharmacokinetics and dynamics of glibenclamide in normal and diabetic rats. In this respect, administration of glibenclamide (1.4 mg/kg, p.o.) significantly reduced the blood glucose level estimated after an intravenous challenge dose (4 ml/kg) of 50% dextrose. Peak drug effect occurred at about 2 h in the control on diabetic group and this effect was clearly evident over a 6 h period in the diabetic group. The stressed diabetic group showed consistently higher blood glucose level at all time points than the non-stressed diabetic controls. Stress was also associated with significant reductions in glibenclamide C p-max and AUC 0−8 and an increase in the T max . These results suggest that the response to glibenclamide in diabetics may be strongly modified by stress through a number of mechanisms. Changes in the bioavailability of the drug and activation of sympathetic nervous system and the hypothalamic-pituitary-adrenocortical axis are potential candidates. Further clinical and experimental studies in relevant models may, however, be needed to characterize fully and relate this effect to rational pharmacotherapy of type II diabetes.
- Content Type Journal Article
- Pages 371-376
- DOI 10.1007/BF03192296
- Authors
- M. A. Abd Elaziz, Department of Clinical Pharmacy, College of Pharmacy, King Saud University, PO Box 2457, 11451 Riyadh, Saudi Arabia
- A. A. Al-Dhawailie, Department of Clinical Pharmacy, College of Pharmacy, King Saud University, PO Box 2457, 11451 Riyadh, Saudi Arabia
- A. Tekle, Department of Clinical Pharmacy, College of Pharmacy, King Saud University, PO Box 2457, 11451 Riyadh, Saudi Arabia
- Pharmacokinetic parameters and killing rates in serum of volunteers receiving amoxicillin, cefadroxil or cefixime alone or associated with niflumic acid or paracetamol
Summary Pharmacokinetic parameters and killing rates in serum of volunteers receiving amoxicillin, cefadroxil or cefixime alone or associated with niflumic acid or paracetamol were studied. Niflumic acid (250 mg) or analgesic and antipyretic drugs such as paracetamol (500 mg) are often combined with antibiotics to avoid inflammation and pain in acute ear, nose and throat diseases. Pharmacokinetic interactions between these two classes of drugs have been described in experimental models, and exceptionally in humans. The aim of the present investigation was to study the interactions of these two drugs with three antibiotics (amoxicillin 500 mg×2, cefadroxil 500 mg×2, cefixime 200 mg and one placebo capsule) on pharmacodynamic parameters and on rate of killing in the serum of six healthy volunteers receiving the antibiotic associated or not with the product in a randomized cross-over double-blind trial. The bacteria most often involved in sinusitis, bronchitis and otitis media ( Haemophilus influenzae, Streptococcus pneumoniae, Staphylococcus aureus ) three target diseases for oral cephalosporins and amoxicillin, were chosen for bacteriological study. Blood samples were obtained at 0.25, 0.50, 1, 1.5, 2, 4, 6 and 12 after oral administration of antibiotics alone or associated with the drugs. There was a wash-out period of at least 1 week between the eleven sequences. Antibiotics were measured by two methods: bioassay and high performance liquid chromatography (HPLC). All serum samples obtained at peak level, 4 and 6 h were tested for killing rate. Area under the time kill curve was calculated by the trapezoidal rule method and relative bioactivity in percent was defined as follows: (AUC control — AUC test)/AUC control × 100. No pharmacokinetic interaction was found in the AUC and T 1/2 of the plasma concentrations of the antibiotics or associated with the drugs, regardless of dose, as determined by HPLC or microbiological assay. For these β-lactam antibiotics killing rate was found to be time-dependent. Bactericidal activity was improved on H. influenzae when cefixime was associated with niflumic acid and became concentration-dependent. A significant concentration relation was also found with niflumic acid or paracetamol associated with cefixime on Strep. pneumoniae .
- Content Type Journal Article
- Pages 357-366
- DOI 10.1007/BF03192294
- Authors
- H. Carsenti-Etesse, University Hospital, Archet, Nice, France
- R. Farinotti, Inserm U13, Bichat Claude Bernard, Paris, France
- J. Durant, University Hospital, Archet, Nice, France
- P. M. Roger, University Hospital, Archet, Nice, France
- F. De Salvador, University Hospital, Archet, Nice, France
- E. Bernard, University Hospital, Archet, Nice, France
- B. Rouveix, Inserm U13, Bichat Claude Bernard, Paris, France
- P. Dellamonica, University Hospital, Archet, Nice, France
- Pharmacokinetics of [125I]-recombinant human interleukin-11:
Summary Placental transfer and excretion into milk of [ 125 I]-rhIL-11 (recombinant human interleukin-11) after subcutaneous administration in female rats were investigated. After administration of [ 125 I]-rhIL-11 to rats on the 14th day of gestation, radioactivity in the kidney was the highest among excised tissues, being 3 times higher than that in the plasma at 1.5 h. Radioactivity in other tissues, including the mammary gland, ovary, uterus, placenta and amniotic fluid, was lower than that in the plasma. Although radioactivity in fetuses was detected 6 h after administration, the level was only 2% of the plasma concentration in dams, and the radioactivity was not found in fetal-derived TCA precipitates. These results indicate that rhIL-11 does not readily pass through the placenta into the fetus. After subcutaneous administration of [ 125 I]-rhIL-11 to lactating rats 14 days after delivery, radioactivity in milk was 1.1–1.6 times that in the plasma of dams. Radioactivity in clotted milk in the stomachs of suckling infants was almost equal to that in the dam’s milk; however, only a small amount of radioactivity was detected in infant kidneys.
- Content Type Journal Article
- Pages 411-416
- DOI 10.1007/BF03192302
- Authors
- T. Uchida, Drug Metabolism Laboratories, Yamanouchi Pharmaceutical Co. Ltd, 1-8, Azusawa 1-chome, Itabashi-ku, 174-8511 Tokyo, Japan
- K. Aoyama, Drug Metabolism Laboratories, Yamanouchi Pharmaceutical Co. Ltd, 1-8, Azusawa 1-chome, Itabashi-ku, 174-8511 Tokyo, Japan
- K. Mori, Drug Metabolism Laboratories, Yamanouchi Pharmaceutical Co. Ltd, 1-8, Azusawa 1-chome, Itabashi-ku, 174-8511 Tokyo, Japan
- T. Usui, Drug Metabolism Laboratories, Yamanouchi Pharmaceutical Co. Ltd, 1-8, Azusawa 1-chome, Itabashi-ku, 174-8511 Tokyo, Japan
- T. Watanabe, Drug Metabolism Laboratories, Yamanouchi Pharmaceutical Co. Ltd, 1-8, Azusawa 1-chome, Itabashi-ku, 174-8511 Tokyo, Japan
- Y. Takariki, Tsukuba Laboratory, Life Science Laboratory, Nemoto & Co., Ltd, Mitsukaido, Ibaraki, Japan
- N. Asahara, Tsukuba Laboratory, Life Science Laboratory, Nemoto & Co., Ltd, Mitsukaido, Ibaraki, Japan
- M. Hirose, Tsukuba Laboratory, Life Science Laboratory, Nemoto & Co., Ltd, Mitsukaido, Ibaraki, Japan
- T. Kimura, Tsukuba Laboratory, Life Science Laboratory, Nemoto & Co., Ltd, Mitsukaido, Ibaraki, Japan
- M. Tateishi, Tsukuba Laboratory, Life Science Laboratory, Nemoto & Co., Ltd, Mitsukaido, Ibaraki, Japan
- S. Higuchi, Drug Metabolism Laboratories, Yamanouchi Pharmaceutical Co. Ltd, 1-8, Azusawa 1-chome, Itabashi-ku, 174-8511 Tokyo, Japan
- Human liver microsomal metabolism of paclitaxel and drug interactions
Summary The aim of this study was to investigate the influence of several anticancer drugs and investigational multidrug resistance (MDR) reversing agents on the hepatic metabolism of paclitaxel (Taxol) to its primary metabolites, 6 α-hydroxypaclitaxel (metabolite, M A ) and 3′-p-hydroxypaclitaxel (metabolite, M B ). There is significant inter-individual variability associated with the levels of these two metabolites. In many cases, 6α-hydroxypaclitaxel has been observed to be the predominant metabolite, in others, 3′-p-hydroxypaclitaxel has been the principal metabolite. The formation of 6α-hydroxypaclitaxel and 3′- p -hydroxypaclitaxel is catalyzed by cytochrome P450 isozymes CYP2C8 and CYP3A4, respectively. A number of factors, including co-administration of drugs and adjuvants, are known to influence the activity of these isozymes. Therefore, the influence of MDR reversing agents, R-verapamil, cyclosporin A (CsA) and tamoxifen and anti-cancer drugs doxorubicin, etoposide (VP-16) and cisplatin on paclitaxel metabolism was assessed employing human liver microsomes in vitro. Paclitaxel (10 μM) was incubated with human liver microsomes (1 mg protein, −0.34 nmol CYP) in the presence of a NADPH generating system at 37°C for 1 h, with and without the presence of interacting drug. Controls included incubations with quercetin and ketoconazole, known inhibitors of 6α-hydroxypaclitaxel and 3′- p -hydroxypaclitaxel formation, respectively. At the end of the incubation period, paclitaxel and the metabolites were extracted in ethyl acetate and analyzed employing an HPLC method. Significant inhibition of paclitaxel conversion to 6α-hydroxypaclitaxel and 3′- p -hydroxypaclitaxel was observed in the presence of R-verapamil, tamoxifen and VP-16 ( P 0.005). Doxorubicin significantly inhibited the formation of 3′- p -hydroxypaclitaxel and CsA inhibited the formation of 6α-hydroxypaclitaxel ( P 0.005). This study demonstrates that co-administration of several of the above listed compounds could lead to significant changes in the pharmacokinetics of paclitaxel.
- Content Type Journal Article
- Pages 417-424
- DOI 10.1007/BF03192303
- Authors
- P. B. Desai, Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati Medical Center, 3223 Eden Avenue, 45267-0004 Cincinnati, OH USA
- J. Z. Duan, Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati Medical Center, 3223 Eden Avenue, 45267-0004 Cincinnati, OH USA
- Y -W. Zhu, Division of Pharmaceutical Sciences, College of Pharmacy, University of Cincinnati Medical Center, 3223 Eden Avenue, 45267-0004 Cincinnati, OH USA
- S. Kouzi, Division of Basic Pharmaceutical Sciences, School of Pharmacy, Northeast Louisiana University, Monroe, Louisiana USA
- The contribution of the enzymes CYP2D6 and CYP2C19 in the demethylation of artemether in healthy subjects
Summary The contribution of the enzymes CYP2D6 and CYP2C19 to the metabolism of artemether was evaluated in a cross-over study in seven healthy adult Caucasian subjects. The pharmacokinetic properties of artemether and its active metabolite dihydroartemisinin were compared when given 100 mg artemether orally alone or in combination with either CYP2D6-inhibitor quinidine or CYP2C19-inhibitor omeprazole. Plasma concentrations of artemether and dihydroartemisinin were measured with reversed phase high performance liquid chromatography with electro-chemical detection (HPLC-ED). Artemether was rapidly absorbed with a mean t max of 0.8 h (95% confidence interval, CI=0.5–1.1) reaching a mean C max of 29 ng/ml (14–45 ng/ml). The mean elimination half-life was 1.3 h (0.8–1.8 h). The pharmacokinetic parameters for dihydroartemisinin were not significantly different from those for artemether. Artemether combined with quinidine revealed no significant changes in the plasma concentrations of either artemether or dihydroartemisinin. No changes were seen in the combination with omeprazole as a CYP2C19 inhibitor. A second peak in the plasma concentration profile was observed 2–4 h after drug intake. This phenomenon was possibly related to variable gastric emptying. No major contribution of the enzymes CYP2D6 or CYP2C19 was found in artemether metabolism. No interethnic differences in artemether metabolism on the basis of a genetic polymorphism of these enzymes is to be expected.
- Content Type Journal Article
- Pages 429-436
- DOI 10.1007/BF03192305
- Authors
- M. A. Van Agtmael, Department of Clinical Pharmacology and Pharmacotherapy, Academic Medical Centre, Meibergdreef 9, 1105 Amsterdam, The Netherlands
- C. A. A. Van Der Graaf, Department of Clinical Pharmacology and Pharmacotherapy, Academic Medical Centre, Meibergdreef 9, 1105 Amsterdam, The Netherlands
- T. K. Dien, Department of Clinical Pharmacology and Pharmacotherapy, Academic Medical Centre, Meibergdreef 9, 1105 Amsterdam, The Netherlands
- R. P. Koopmans, Department of Clinical Pharmacology and Pharmacotherapy, Academic Medical Centre, Meibergdreef 9, 1105 Amsterdam, The Netherlands
- C. J. Van Boxtel, Department of Clinical Pharmacology and Pharmacotherapy, Academic Medical Centre, Meibergdreef 9, 1105 Amsterdam, The Netherlands
- Species differences in the metabolic activation of tamoxifen into genotoxic derivatives: risk assessment in women
Summary Rats and Rhesus monkeys are compared in their response to tamoxifen treatment, with particular reference to tamoxifen-related liver DNA damage and bioactivation of tamoxifen by isolated microsomes in vitro. Monkeys, treated with tamoxifen, accumulate in their livers a metabolite of tamoxifen, N,N-didesmethyl tamoxifen, with powerful inhibitory activity on cytochrome P450-dependent drug metabolism. The accumulation of this metabolite in the monkeys may limit the cytochrome P450-dependent conversion of tamoxifen into reactive derivatives and, in this way, protect against the formation of DNA adducts. This metabolite is also found in the liver and serum of patients taking tamoxifen, but more work is needed to determine whether inhibition of tamoxifen bioactivation also exists in the human patient in vivo and, if so, to what extent and in which organ.
- Content Type Journal Article
- Pages 425-428
- DOI 10.1007/BF03192304
- Authors
- F. De Matteis, Department of Anatomy, Pharmacology and Forensic Medicine, University of Turin Medical School, Turin, Italy
- I. N. H. White, Medical Research Council Toxicology Unit, University of Leicester, Leicester, UK
- L. L. Smith, Medical Research Council Toxicology Unit, University of Leicester, Leicester, UK
- Events
<p class="abstract">Events</p><ul>
<li><span class="labelName">Content Type </span><span class="labelValue">Journal Article</span></li><li>Pages 437-438</li><li>DOI 10.1007/BF03192306</li>
</ul><ul class="parents">
<ul class="details">
<li><span class="header labelName">Journal </span><span class="labelValue"><a href="http://www.springerlink.com/content/121759/">European Journal of Drug Metabolism and Pharmacokinetics</a></span></li><li><span class="labelName">Online ISSN </span><span class="labelValue">2107-0180</span></li><li><span class="labelName">Print ISSN </span><span class="labelValue">0378-7966</span></li>
</ul><ul class="details">
<li><span class="header labelName">Journal Volume </span><span class="labelValue">Volume 23</span></li>
</ul><ul class="details">
<li><span class="header labelName">Journal Issue </span><span class="labelValue"><a href="http://www.springerlink.com/content/xvp40t3424t6/">Volume 23, Number 3</a></span></li>
</ul>
</ul>
- Absolute bioavailability of [14C] genistein in the rat; plasma pharmacokinetics of parent compound, genistein glucuronide and total radioactivity
Summary The systemic plasma pharmacokinetics of genistein were determined in rats to evaluate the absolute oral bioavailability and make comparison with similar data in the literature derived from humans subjects. The plasma concentrations of genistein, genistein glucuronide and carbon-14 were determined by LC-MS/MS and liquid scintillation counting following oral and intravenous dosing with [ 14 C]genistein (4 mg kg −1 body weight). The absorption of total radioactivity from the gut, (parent compound and metabolites), was 56 and 111% in male and female rats, respectively. In contrast, the absolute oral bioavailability of genistein in male and female rats was 7 and 15%. There was a significant (P<0.001) difference between C max of genistein after intravenous (6921 and 4392 ng/ml) and oral (21 and 22 ng/ml) dosing in male and female rats, respectively. After oral administration, the concentration profile of genistein glucuronide in plasma greatly exceeded that of parent compound during the absorption/distribution phase suggesting extensive first pass metabolism, and provided evidence of entero-hepatic circulation. Selective plasma analysis by LC-MS/MS, without prior enzymatic hydrolysis, enabled ready discrimination between parent and conjugated metabolites and prevented gross overestimation of genistein bioavailability. Pharmacokinetic parameters C max , T max and AUC were similar to those reported in humans, which supports the use of the rat model for genistein toxicity studies.
- Content Type Journal Article
- Pages 249-258
- DOI 10.1007/BF03192335
- Authors
- Nick G. Coldham, Department of Risk Research, Veterinary Laboratories Agency, KT15 3NB Addlestone, Surrey U.K.
- Ai-Qin Zhang, Department of Risk Research, Veterinary Laboratories Agency, KT15 3NB Addlestone, Surrey U.K.
- Pauline Key, Nutrition and Consumer Science, Institute of Food Research, Norwich Research Park, Colney, NR4 7UA Norwich, U.K.
- Maurice J. Sauer, Department of Risk Research, Veterinary Laboratories Agency, KT15 3NB Addlestone, Surrey U.K.
- Comparison of MEGX (monoethylglycinexylidide) and antipyrine tests in patients with liver cirrhosis
Summary The aim of the study was to compare the feasibility of the MEGX (monoethylglycinexylidide) and antipyrine tests in reference to standard biochemical parameters used for liver assessment in cirrhotic patients. The study was carried out in 44 subjects: 14 healthy controls and 30 cirrhotic patients classified according to the Child-Pugh’s score to subgroups A (n=11), B (n=12) and C (n=7). All subjects underwent two dynamic liver tests, i.e. MEGX (monoethylglycinexylidide) and antipyrine test in a crossover schedule with at least 5-day interval. For the MEGX, lidocaine was administrated intravenously, at a dose of 1 mg/kg, and blood samples for MEGX assay were collected after 15 minutes. MEGX concentrations were measured by fluorescence polarization immunoassay. The antipyrine concentrations were evaluated following a single oral administration of 1000 mg antipyrine. The blood was sampled for 24 hours after the drug administration, and antipyrine concentrations were measured spectrophotometrically. Standard biochemical parameters used for liver assessment were measured by means of routine laboratory methods. It was concluded that in patients liver with cirrhosis, liver dynamic tests were better predictors of hepatic function. The MEGX test was more feasible in clinical setting, but it was noted that antipyrine test was more sensitive in staging liver cirrhosis.
- Content Type Journal Article
- Pages 243-247
- DOI 10.1007/BF03192334
- Authors
- J. Wojcicki, Department of Experimental and Clinical Pharmacology, Pomeranian Academy of Medicine, Powstancow Wlkp. 72, 70-111 Szczecin, Poland
- K. Kozlowski, Department of General and Transplantation Surgery, Pomeranian Academy of Medicine, Poland
- M. Drozdzik, Department of Experimental and Clinical Pharmacology, Pomeranian Academy of Medicine, Powstancow Wlkp. 72, 70-111 Szczecin, Poland
- M. Wojcicki, Department of General and Transplantation Surgery, Pomeranian Academy of Medicine, Poland
- Comparison of in vitro hepatic models for the prediction of metabolic interaction between simvastatin and naringenin
Summary The study of potential interaction at a very early stage of drug development requires suitable in vitro models that describe drug interactions both qualitatively and quantitatively. The purpose of this work was to help assessing the predictive value of in vitro drug interaction test with liver microsomal fractions and hepatocytes by determination of enzymatic parameters such as the inhibition constant (Ki) and the intrinsic clearance (Clint). This study was conducted to compare different methods of Ki calculation and to determine the most suitable parameter for describing drug interactions. The metabolic interaction between SV and NRG was used as a model to help verifying the suitability of the in vitro model for predicting the kind and degree of metabolic drug interactions. The method of Ki calculation using linearized versions of Michaelis Menten equations based on the simultaneous non linear regressions and the “km app” approach accurately estimated the Ki values. The linear representation of an inherently non linear relationship was only used to establish the mechanism of inhibition and the Clint could be used to predict drug interactions. To further prediction in humans, it seems likely that the simultaneous application of both systems, microsomal fractions and hepatocytes will yield conclusions.
- Content Type Journal Article
- Pages 233-241
- DOI 10.1007/BF03192333
- Authors
- N. Le Goff, Laboratory of Therapeutic Chemistry, Faculty of Pharmacy, University Louis Pasteur, Strasbourg, France
- J. C. Koffel, Laboratory of Therapeutic Chemistry, Faculty of Pharmacy, University Louis Pasteur, Strasbourg, France
- S. Vandenschrieck, Laboratory of Therapeutic Chemistry, Faculty of Pharmacy, University Louis Pasteur, Strasbourg, France
- L. Jung, Laboratory of Therapeutic Chemistry, Faculty of Pharmacy, University Louis Pasteur, Strasbourg, France
- G. Ubeaud, Laboratory of Therapeutic Chemistry, Faculty of Pharmacy, University Louis Pasteur, Strasbourg, France
- Stress-induced lidocaine modification in serum and tissues
Summary The aim of this study is to examine the influence of acute (trauma) and chronic (cold swimming and adjuvant rheumatoid arthritis) stress on lidocaine concentrations in plasma. Forty male Wistar rats were used. The animals were divided into four groups. Group A served as control. Group B underwent mandible osteotomy. Group C was submitted to swimming stress in cold water 4°C for ten minutes daily for 15 minutes, while group D underwent experimental arthritis with Freud’s adjuvant. All groups received lidocaine i.m (2.5 mg/kg). Blood samples were collected and FFA (free fatty acid), unbound-lidocaine, albumin and a 1 -acid glycoprotein concentrations were estimated. Furthermore, the adrenals, heart and liver were isolated. The adrenals’ relative weight (adrenal weight/body weight) was assessed, while lidocaine concentrations in the heart and the liver incubation medium were measured by intertechnic a-counter. Lidocaine and FFA levels in serum as well as the adrenal weights demonstrated a significant elevation in stress-groups as compared to the control group. Furthermore, in the stress-groups, lidocaine concentrations in heart tissue were significantly increased, whereas in the liver they were significantly reduced as compared to the control group. Our results indicate that stress can alter lidocaine levels in plasma and tissues, suggesting that stress should be considered an important factor when determining the dosage of lidocaine in clinical application.
- Content Type Journal Article
- Pages 229-232
- DOI 10.1007/BF03192332
- Authors
- T. Saranteas, Department of Pharmacology, Medical School, University of Athens, M. Asias 75, 11527 Goudi, Greece
- C. Tesseromatis, Department of Pharmacology, Medical School, University of Athens, M. Asias 75, 11527 Goudi, Greece
- A. Potamianou, Department of Pharmacology, Medical School, University of Athens, M. Asias 75, 11527 Goudi, Greece
- C. Mourouzis, Department of Pharmacology, Medical School, University of Athens, M. Asias 75, 11527 Goudi, Greece
- D. Varonos, Department of Pharmacology, Medical School, University of Athens, M. Asias 75, 11527 Goudi, Greece
- Tissue pharmacokinetics of florfenicol in pigs experimentally infected with Actinobacillus pleuropneumoniae
Summary The aim of this study has been to determine the tissue pharmacokinetic parameters of florfenicol in the pigs experimentally infected with Actinobacillus pleuropneumoniae. 21 crossed-bred (Duroc × Landrace × Yorkshire) local species of pigs were infected experimentally with Actinobacillus pleuropneumoniae serotype 1 and confirmed as typical sub-acute pleuropneumonia. A single dose of 20mg/kg body weight of florfenicol, a novel animal-using antibiotic, was administrated intramuscularly in the pigs and then samples of blood, lung, trachea with bronchi, liver, kidney and muscle were taken at scheduled time points. Drug concentrations were determined by high performance liquid chromatography (HPLC) with an ultraviolet detector via extraction with ethyl acetate under nitrogen flow. The statistic moment theory (SMT) mathematic package was applied to calculate the tissue pharmacokinetic parameters of florfenicol in the infected model. AUC of lung, trachea with bronchi, liver, kidney and muscle were 121.69, 79.37, 81.05, 181.2, and 94.07 mg/l-h, respectively, MRT were from 34.66 to 90.17 h, and t 1/2β from 24.75 to 69.34 h, respectively. Conclusions: Florfenicol was widely distributed in these tissues and maintained the effective therapeutic concentrations especially in the respiratory tract tissues that are the target organs of Actinobacillus pneuropneumoniae. Clinical significance: Tissue pharmacokinetic data could be evidence for regime designing of florfenicol in treatment of porcine pleuropneumonia
- Content Type Journal Article
- Pages 265-271
- DOI 10.1007/BF03192337
- Authors
- Jian-Zhong Liu, Division of Pharmacology and Clinical Pharmacology, Faculty of Medical and Health Sciences, The University of Auckland, Private Bag 92019, Auckland, New Zealand
- Ki-Fai Fung, Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, South China Agricultural University, Guangzhou, PR China
- Zhang-Liu Chen, Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, South China Agricultural University, Guangzhou, PR China
- Zhen-Ling Zeng, Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, South China Agricultural University, Guangzhou, PR China
- Jie Zhang, Laboratory of Veterinary Pharmacology, College of Veterinary Medicine, South China Agricultural University, Guangzhou, PR China
No Issue Number - Pharmacokinetics and tissue distribution of 25-hydroxyprotopanaxadiol, an anti-cancer compound isolated from Panax ginseng, in athymic mice bearing xenografts of human pancreatic tumors
Abstract To determine pharmacokinetics and tissue distribution of 25-hydroxyprotopanaxadiol [25-OH-PPD, 20( R )-dammarane-3β,12β,20,25-tetrol], a promising antitumor natural product isolated from the fruits of Panax ginseng , an analytical method involving liquid chromatography/tandem mass spectrometry in biological samples was developed and employed. After intravenous and oral administration to nude mice bearing xenografts of human pancreatic tumors at doses of 10 and 20 mg/kg body weight, respectively, 25-OH-PPD was rapidly absorbed and distributed in plasma and in all tissues examined, including the tumors, with all C max > 2 μg/ml or μg/g and t max <1 h. The absolute oral bioavailability of 25-OH-PPD was relatively high, compared with other ginsenosides. These results indicate that this novel anti-cancer ginsenoside has relatively favorable pharmacokinetic properties and provide a basis for further development of this compound as a chemotherapeutic agent.
- Content Type Journal Article
- Pages 109-113
- DOI 10.1007/s13318-010-0022-9
- Authors
- Miao Hao, Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate School of the Chinese Academy of Sciences, Rm 427, Building 41, 320 Yueyang Road, Shanghai, 200031 People’s Republic of China
- Wei Wang, Department of Pharmaceutical Sciences, Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
- Yuqing Zhao, Shenyang Pharmaceutical University, Shenyang, 110016 People’s Republic of China
- Ruiwen Zhang, Department of Pharmaceutical Sciences, Cancer Biology Center, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA
- Hui Wang, Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Graduate School of the Chinese Academy of Sciences, Rm 427, Building 41, 320 Yueyang Road, Shanghai, 200031 People’s Republic of China
- Assessment and modulation of phillyrin absorption by P-gp using Caco-2 cells and MDR1-MDCKII cells
Abstract The study was to investigate the absorption mechanism and transport modulation of phillyrin by P-gp in Caco-2 cells and MDR1-MDCKII cells. Three concentrations of phillyrin were tested in transport studies. The absorptive transports of phillyrin in the two cell models were not concentration-dependent which indicated passive diffusion as the dominating process in the test concentrations. The absorptive P app were 7.15, 6.39 and 10.03 × 10 −6 cm s −1 , respectively, for different concentrations (2.2, 4.8 and 8.4 μg ml −1 ) in Caco-2 cells. And the low absorptive P app was consistent with the low oral bioavailability of phillyrin observed in pharmacokinetic experiments. In transport inhibition experiment, the efflux inhibitors, verapamil and GF120918 can increase the absorption of phillyrin in Caco-2 cells which suggested the involvement of efflux transporters. In the further inhibition experiment in MDR1-MDCKII cells, the absorption was greatly increased and the efflux of phillyrin was competitively inhibited by verapamil and GF120918, which confirmed the involvement of P-gp in the efflux of phillyrin.
- Content Type Journal Article
- Pages 1-7
- DOI 10.1007/s13318-011-0026-0
- Authors
- Yun-Xia Li, Pharmacy College, Chengdu University of Traditional Chinese Medicine, No. 1166, Liutai Road, Chengdu, 610075 People’s Republic of China
- Liang-Hong Ye, Pharmacy College, Chengdu University of Traditional Chinese Medicine, No. 1166, Liutai Road, Chengdu, 610075 People’s Republic of China
- Xue-Hua Jiang, West China School of Pharmacy, Sichuan University, Chengdu, 610041 People’s Republic of China
- Cheng Peng, Pharmacy College, Chengdu University of Traditional Chinese Medicine, No. 1166, Liutai Road, Chengdu, 610075 People’s Republic of China
- Evaluation of the pharmacokinetic interaction after multiple oral doses of linagliptin and digoxin in healthy volunteers
Abstract The aim of this study was to investigate whether multiple doses of the oral and highly selective dipeptidyl peptidase-4 inhibitor linagliptin affect the steady-state pharmacokinetics of the P-glycoprotein substrate digoxin. This single-center, open-label, two-period cross-over study involved healthy subjects ( n = 20), randomized to treatment sequence AB or BA, where A comprised 0.25 mg digoxin qd for 5 days, then 0.25 mg digoxin qd plus 5 mg linagliptin qd for 6 days, and B comprised 0.25 mg digoxin qd for 11 days. A treatment-free period (≥35 days for AB and 14 days for BA) separated each treatment in both sequences. There were no clinically significant changes in steady-state pharmacokinetic parameters of digoxin when it was co-administered with linagliptin. The ratio of the adjusted-by-treatment geometric mean ratios and associated 90% confidence intervals for the AUC τ,ss , C max,ss and renal clearance (CL R ,0 – 24,ss ) of digoxin were all within the bioequivalence range 80–125%, which is important as digoxin has a narrow therapeutic range. There was a low incidence of adverse events, which were randomly distributed between treatment groups. In conclusion, linagliptin did not alter the pharmacokinetics of digoxin in this study, indicating that linagliptin does not inhibit P-glycoprotein or other transporters relevant for digoxin pharmacokinetics. These results suggest that linagliptin and digoxin can be co-administered without dose adjustment. Administration of digoxin alone and with linagliptin was well tolerated.
- Content Type Journal Article
- Pages 1-8
- DOI 10.1007/s13318-011-0028-y
- Authors
- C. Friedrich, Translational Medicine, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach, Germany
- A. Ring, Translational Medicine, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach, Germany
- T. Brand, Translational Medicine, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach, Germany
- R. Sennewald, Translational Medicine, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach, Germany
- E. U. Graefe-Mody, Translational Medicine, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach, Germany
- H.-J. Woerle, Translational Medicine, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88397 Biberach, Germany
- Prediction tacrolimus blood levels based on the Bayesian method in adult kidney transplant patients
Abstract The use of tacrolimus is complicated by its narrow therapeutic index and wide intra- and interpatient variability. We have previously described a tacrolimus population pharmacokinetics model obtained in an adult kidney transplant cohort. The aims of the present study were (1) to validate that model using an external dataset and (2) to evaluate the prediction using a Bayesian method. Data were retrospectively collected from 34 adult patients receiving kidney transplantation. Trough blood concentrations of tacrolimus were predicted using the empirical Bayesian method with sparse samples obtained during the previous week. The system performance was evaluated by the mean prediction error (ME), mean absolute prediction error (MAE). and root mean square error (RMSE). Patients were administrated oral or intravenous tacrolimus as part of a triple immunosuppressive regimen with mycophenolate mofetil and corticosteroids. Subsequent doses were adjusted on the basis of clinical evidence of efficacy and toxicity and by routine therapeutic drug monitoring. In our previous model, clearance increased with post transplantation days and with prednisone dosage. Concentrations predicted by the population mean pharmacokinetic parameter values match well with observed concentrations during oral therapy. Bayesian prediction using trough concentrations obtained after 21 days of treatment significantly decreased ME, MAE, and RMSE compared with predictions from data including this period. After 21 days of treatment, there was an insignificant bias ME (0.22 ± 2.59 ng/ml), a reasonable precision MAE (1.97 ± 1.69 ng/ml) and RMSE (1.28 ± 0.58 ng/ml). The present study demonstrates the suitability of the Bayesian method for the prediction of trough blood concentrations of tacrolimus using only few samples in adult kidney transplantation recipients.
- Content Type Journal Article
- Pages 1-9
- DOI 10.1007/s13318-011-0027-z
- Authors
- Marie Antignac, Pharmacy Department, Pitié Salpêtrière Hospital AP-HP, 47 Bd de l’Hôpital, 75013 Paris, France
- Christine Fernandez, Pharmacy Department, Pitié Salpêtrière Hospital AP-HP, 47 Bd de l’Hôpital, 75013 Paris, France
- Benoît Barrou, INSERM U927 - Paris VI University, Department of Urology Surgery, Pitié Salpêtrière Hospital AP-HP, 47 Bd de l’Hôpital, 75013 Paris, France
- Mariona Roca, Pharmacy Department, Pitié Salpêtrière Hospital AP-HP, 47 Bd de l’Hôpital, 75013 Paris, France
- Jean-Louis Favrat, Pharmacy Department, Pitié Salpêtrière Hospital AP-HP, 47 Bd de l’Hôpital, 75013 Paris, France
- Saïk Urien, CIC 0901 INSERM EA3620 Paris V University, TARNIER Hospital AP-HP, 89 Rue d’Assas, 75006 Paris, France
- Robert Farinotti, Pharmacy Department, Pitié Salpêtrière Hospital AP-HP, 47 Bd de l’Hôpital, 75013 Paris, France
- Chemical inhibitors of cytochrome P450 isoforms in human liver microsomes: a re-evaluation of P450 isoform selectivity
Abstract The majority of marketed small-molecule drugs undergo metabolism by hepatic Cytochrome P450 (CYP) enzymes (Rendic 2002 ). Since these enzymes metabolize a structurally diverse number of drugs, metabolism-based drug–drug interactions (DDIs) can potentially occur when multiple drugs are coadministered to patients. Thus, a careful in vitro assessment of the contribution of various CYP isoforms to the total metabolism is important for predicting whether such DDIs might take place. One method of CYP phenotyping involves the use of potent and selective chemical inhibitors in human liver microsomal incubations in the presence of a test compound. The selectivity of such inhibitors plays a critical role in deciphering the involvement of specific CYP isoforms. Here, we review published data on the potency and selectivity of chemical inhibitors of the major human hepatic CYP isoforms. The most selective inhibitors available are furafylline (in co-incubation and pre-incubation conditions) for CYP1A2, 2-phenyl-2-(1-piperidinyl)propane (PPP) for CYP2B6, montelukast for CYP2C8, sulfaphenazole for CYP2C9, (–)- N -3-benzyl-phenobarbital for CYP2C19 and quinidine for CYP2D6. As for CYP2A6, tranylcypromine is the most widely used inhibitor, but on the basis of initial studies, either 3-(pyridin-3-yl)-1 H -pyrazol-5-yl)methanamine (PPM) and 3-(2-methyl-1H-imidazol-1-yl)pyridine (MIP) can replace tranylcypromine as the most selective CYP2A6 inhibitor. For CYP3A4, ketoconazole is widely used in phenotyping studies, although azamulin is a far more selective CYP3A inhibitor. Most of the phenotyping studies do not include CYP2E1, mostly because of the limited number of new drug candidates that are metabolized by this enzyme. Among the inhibitors for this enzyme, 4-methylpyrazole appears to be selective.
- Content Type Journal Article
- Pages 1-16
- DOI 10.1007/s13318-011-0024-2
- Authors
- Siamak Cyrus Khojasteh, Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
- Saileta Prabhu, Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
- Jane R. Kenny, Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
- Jason S. Halladay, Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080, USA
- Anthony Y. H. Lu, Department of Chemical Biology, Ernest Mario College of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA
- Effect of blood decrease on micafungin disposition in rats
Abstract Micafungin (MCFG) is a novel echinocandin-class antifungal agent that extensively undergoes metabolic removal in the liver. In the present study, the influence of decreased blood volume on pharmacokinetic disposition of MCFG was examined using a rat model prepared by phlebotomy. In phlebotomized rats, hematocrit level and plasma albumin concentration were decreased by 50 and 15%, respectively. Regarding the pharmacokinetic parameters of MCFG, there were no significant differences in the total body clearance (CL tot ) and elimination rate constant ( k e ) between control and phlebotomized rat groups. A slight increase was observed in the apparent volume of distribution at steady-state (Vd ss ), but the degree of change was minimal. These findings demonstrate that the elimination capacity for MCFG is only slightly affected by severe anemia and moderate hypoalbuminemia, and provide experimental evidence for the preceding clinical studies suggesting that neither hematocrit level nor serum albumin concentration is a contributory factor for the metabolic clearance of MCFG.
- Content Type Journal Article
- Pages 1-5
- DOI 10.1007/s13318-011-0023-3
- Authors
- Hiroki Konishi, Laboratory of Clinical Pharmacy and Therapeutics, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, 548-8540 Japan
- Keizo Fukushima, Department of Hospital Pharmacy, Shiga University of Medical Science, Otsu, Japan
- Masatomo Sudo, Department of Hospital Pharmacy, Shiga University of Medical Science, Otsu, Japan
- Masaki Sumi, Department of Hospital Pharmacy, Shiga University of Medical Science, Otsu, Japan
- Tokuzo Minouchi, Department of Hospital Pharmacy, Shiga University of Medical Science, Otsu, Japan
- Ikumi Iga, Laboratory of Clinical Pharmacy and Therapeutics, Faculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-kita, Tondabayashi, 548-8540 Japan
- Nobuhito Shibata, Department of Biopharmaceutics, Faculty of Pharmaceutical Sciences, Doshisha Women’s College of Liberal Arts, Kyotanabe, Japan
- Akira Yamaji, Department of Hospital Pharmacy, Shiga University of Medical Science, Otsu, Japan
- The rationality for using prodrug approach in drug discovery programs for new xenobiotics: opportunities and challenges
Abstract The concept of prodrugs has been successfully executed for life cycle management options of several approved drugs and drugs in development. In addition to imparting ideal biopharmaceutical properties, such as solubility, permeability and lipophilicity, some prodrug concepts have also enabled site-specific drug delivery, prolonged the duration of therapeutic effect and improved therapeutic index. The strategic inclusion of prodrug concept during drug discovery and early development process brings in some unique challenges. The communication provides balanced perspectives on the rational use and challenges of prodrug concept during the drug discovery and development process.
- Content Type Journal Article
- Pages 1-11
- DOI 10.1007/s13318-011-0035-z
- Authors
- Nuggehally R. Srinivas, Vanthys Pharmaceutical Development (Pvt) Ltd, #46, 3rd Floor, Phoenix Pinnacle, Ulsoor Road, Bangalore, 560042 India
- Investigation on the absorption of phillyrin and forsythiaside in rat digestive tract
Abstract In the present study, an in situ rat model was employed to systemically investigate the absorption of phillyrin and forsythiaisde. Three concentrations of phillyrin (0.2, 0.4 and 1.5 mg) were tested and the results showed that phillyrin cannot be absorbed in the digestive tract. The absorption rates of forsythiaside in stomach were 7.773, 7.228 and 6.751% h −1 for 0.5, 1 and 2.5 mg, and no significant difference was found in different concentrations. The absorptions of forsythiaside in intestine were investigated in different concentrations and different absorption sites. The mean P% were 6.618, 7.199, 9.210 and 9.747% h −1 of forsythiaside in intestine for 0.25, 0.5, 1, 2.5 mg dosage, and the statistical analysis showed that the absorption had no relation with concentration. In addition, in different digestive segments, the mean P% were 7.528, 8.382, 8.191, 9.109 and 6.908% h −1 for the gastric, duodenum, jejunum, ileum and colon, respectively. No statistical differences of absorption were found for forsythiaside among different digestive segments indicated no specific absorption site was found.
- Content Type Journal Article
- Pages 1-7
- DOI 10.1007/s13318-011-0031-3
- Authors
- Yun-xia Li, Pharmacy College, Chengdu University of Traditional Chinese Medicine; The Ministry of Education Key Laboratory of Standardization of Chinese Herbal Medicine; State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu, 610075 People’s Republic of China
- Cheng Peng, Pharmacy College, Chengdu University of Traditional Chinese Medicine; The Ministry of Education Key Laboratory of Standardization of Chinese Herbal Medicine; State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu, 610075 People’s Republic of China
- Liang-hong Ye, Pharmacy College, Chengdu University of Traditional Chinese Medicine; The Ministry of Education Key Laboratory of Standardization of Chinese Herbal Medicine; State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu, 610075 People’s Republic of China
- Ruo-qi Zhang, Department of Clinical Pharmacy, West China School of Pharmacy, Sichuan University, No. 17, Section 3, Southern Renmin Road, Chengdu, 610041 People’s Republic of China
- Xue-hua Jiang, Department of Clinical Pharmacy, West China School of Pharmacy, Sichuan University, No. 17, Section 3, Southern Renmin Road, Chengdu, 610041 People’s Republic of China
- Pharmacokinetic study of a novel stroke therapeutic, 2-[[(1,1-dimethylethyl)oxidoimino]methyl]-3,5,6-trimethylpyrazine, by a simple HPLC–UV method in rats
Abstract 2-[[(1,1-dimethylethyl)oxidoimino]methyl]-3,5,6-trimethylpyrazine (TBN), a novel nitrone derivative of tetramethylpyrazine (TMP), was found to be a potent candidate compound for ischemic stroke treatment. It is currently in preclinical development as a stroke therapeutic. To study its pharmacokinetic characteristics, a simple and rapid HPLC–UV method was developed and validated to quantitatively determine TBN concentration in rat plasma. A Purospher C 18 column (150 × 4.6 mm, 5 μm) was used for analysis with a mobile phase containing methanol–potassium dihydrogen phosphate buffer solution (50 mM, pH 3.0) (45:55, v/v) and UV detection at 295 nm. The pharmacokinetic study was conducted in Sprague–Dawley rats by intravenous (i.v. 40, 80, and 160 mg/kg) and intragastric (i.g. 80 mg/kg) administration. The concentration–time profiles of TBN in plasma fitted a two-compartment model for both administration routes. The elimination half-life ( T 1/2 (β)) of i.v. administration ranged from 134 to 225 min for low, middle and high dosage, and the area under the concentration–time curve from zero to infinity (AUC (0–∞) ) ranged from 7,954 to 49,804 μg min/mL. Compared with the parent compound TMP, TBN showed a longer T 1/2 (β) (TBN 134.52 min, TMP 91.85 min) and a higher AUC (0–∞) (TBN 22,687.84 μg min/mL, TMP 7,287.98 μg min/mL) after the same dosage of intravenous administration (80 mg/kg). The intragastric administration of TBN had a peak time of 21.65 min, C max of 41.71 μg/mL, and k a of 0.19 min −1 . And the absolute bioavailability was 36.02%.
- Content Type Journal Article
- Pages 1-7
- DOI 10.1007/s13318-011-0032-2
- Authors
- Sha Li, Jinan University College of Pharmacy and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drug Research, 510632 Guangzhou, People’s Republic of China
- Hainan Chen, Jinan University College of Pharmacy and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drug Research, 510632 Guangzhou, People’s Republic of China
- Xingli Wang, Jinan University College of Pharmacy and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drug Research, 510632 Guangzhou, People’s Republic of China
- Jianfeng Wu, Jinan University College of Pharmacy and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drug Research, 510632 Guangzhou, People’s Republic of China
- Jie Jiang, Jinan University College of Pharmacy and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drug Research, 510632 Guangzhou, People’s Republic of China
- Yuqiang Wang, Jinan University College of Pharmacy and Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drug Research, 510632 Guangzhou, People’s Republic of China
- A bioequivalence study of two tamsulosin sustained-release tablets in Indonesian healthy volunteers
Abstract The bioavailability of two 0.4 mg tamsulosin sustained-release film-coated tablet formulations was compared; using generic tablets (Prostam ® ) as test formulation and the originator product as reference formulation. Twenty-four subjects were included in this single-dose, open-label, randomized two-way crossover design following an overnight fasting. A one-week wash-out period was applied. Blood samples were drawn up to 72 h following drug administration. Plasma concentration of tamsulosin was determined by liquid chromatography–tandem mass spectrometry method with TurboIonSpray mode. Pharmacokinetic parameters AUC 0– t , AUC 0–∞ , C max and t ½ were determined and used for bioequivalence evaluation after log-transformation, whereas t max ratios were evaluated non-parametrically. The estimated point and 90% confidence intervals (CI) for AUC 0– t , AUC 0–∞ , C max and t ½ were 109.55% (96.41–124.49%), 109.94% (96.85–124.81%), 105.87% (92.88–120.67%) and 100.00% (90.56–110.43%), respectively. These results indicated that the two formulations of tamsulosin were bioequivalent; therefore they may be prescribed interchangeably.
- Content Type Journal Article
- Pages 1-5
- DOI 10.1007/s13318-011-0033-1
- Authors
- Budi Prasaja, Clinisindo Laboratories, Jakarta, Indonesia
- Yahdiana Harahap, Department of Pharmacy, Faculty of Mathematic and Science, University of Indonesia, Depok, Indonesia
- Windy Lusthom, Clinisindo Laboratories, Jakarta, Indonesia
- Evy C. Setiawan, Clinisindo Laboratories, Jakarta, Indonesia
- Mena B. Ginting, Clinisindo Laboratories, Jakarta, Indonesia
- Hardiyanti, Clinisindo Laboratories, Jakarta, Indonesia
- Lipin, Clinisindo Laboratories, Jakarta, Indonesia
- Human pharmacokinetics of the muscle relaxant, eperisone hydrochloride by liquid chromatography–electrospray tandem mass spectrometry
Abstract Eperisone hydrochloride (4′-ethyl-2-methyl-3-piperidinopropiophenone hydrochloride) is a muscle relaxant agent, widely used in the treatment of patients with muscular contractures, low back pain or spasticity. Because of its mechanism of action (inhibition of gamma-efferent firing and local vasodilatation activity), side effects on central nervous system are rarely observed. A sensitive liquid chromatography–electrospray ionization-mass spectrometry method for determination of eperisone in human plasma has been developed, with a lower limit of quantification of 0.01 ng/mL. The method was applied to a pharmacokinetic study in 12 healthy volunteers given eperisone 100 mg as single dose on day 1 and three times daily on days 2 to 4. Eperisone was rapidly absorbed after oral administration ( T max = 1.6 h) as it was expected by its fast-onset relaxant activity. Moreover, eperisone underwent a rapid elimination from the body (biological half-life 1.87 h), which was not modified during the repeated dosing as suggested by the C max cumulation observed, not different from that expected for a t 1/2 of 1.87 h as suggested by the similar and negligible plasma concentration values (0.063 and 0.067 ng/mL) measured on day 4 before the morning dose and 12 h after evening dose, thus ruling out any potential risk for drug accumulation. Thus, the pharmacokinetic characteristics of eperisone provide further justification for its tolerability in patients with low back pain or spastic palsy, in which the drug is given for periods ranging from few days to several months, respectively.
- Content Type Journal Article
- Pages 1-8
- DOI 10.1007/s13318-011-0034-0
- Authors
- Barbara Melilli, Pharmacokinetic Unit, Unifarm Research Center, University of Catania, Viale A. Doria 21, 95125 Catania, Italy
- Cateno Piazza, Pharmacokinetic Unit, Unifarm Research Center, University of Catania, Viale A. Doria 21, 95125 Catania, Italy
- Daniela Cristina Vitale, Pharmacokinetic Unit, Unifarm Research Center, University of Catania, Viale A. Doria 21, 95125 Catania, Italy
- Maria Rosa Marano, Pharmacokinetic Unit, Unifarm Research Center, University of Catania, Viale A. Doria 21, 95125 Catania, Italy
- Andrea Pecori, Eisai, Via dell’Unione Europea 6b, 20097 San Donato Milanese Milano, Italy
- Paolo Mattana, Alfa Wassermann, Via Ragazzi del ‘99 n 5, 65020 Bologna, Italy
- Valentina Li Volsi, PhD School of Neuropharmacology, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
- Carmelo Iuculano, PhD School of Neuropharmacology, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
- Francesco Cardì, Polyclinic Vittorio Emanuele University of Catania, Viale S. Sofia 78, 95123 Catania, Italy
- Filippo Drago, Department of Experimental and Clinical Pharmacology, University of Catania, Viale A. Doria 6, 95125 Catania, Italy
- Application of one-compartmental bio-metric blood loss calculations with transfused blood volume taken into account after aneurysmectomy
Abstract Blood loss can be measured directly and indirectly. The latter reflects blood loss through the assessment of hemoglobin level. Thus aim of this study was to determine the applicability of the drop in hemoglobin levels blood loss calculation when transfused blood volume is taken into account on the patients who underwent aneurysmectomy and to estimate whether this model is applicable on geriatric population. In this study, 14 patients were included and their blood loss was calculated based on hemoglobin concentration. Linear correlation ( y = 0.18467 + 1.19315· x ) with high correlation coefficient ( r = 0.90809) was found between calculated and collected blood loss only if transfused blood volume was taken into account. The coefficient of the regression slope for the blood volume measured during surgery and the calculated blood loss in eight patients ≤65 years ( y = 0.90866 + 0.86296· x ) and six patients >65 years ( y = 0.0299 + 1.32707· x ) did not show any significant difference. The applicability of the indirect measurement of surgical blood loss, when transfused blood volume was taken into account, was demonstrated in both populations, in the age of 65 and less and in the age over 65 years after aneurysmectomy.
- Content Type Journal Article
- Pages 1-6
- DOI 10.1007/s13318-011-0025-1
- Authors
- Nataša Božičković, Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Republic of Serbia
- Jovan Popović, Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, Republic of Serbia
- Radmila Kolak, Clinics of Anesthesia and Intensive Care, Medical Faculty, University Hospital of Novi Sad, Novi Sad, Republic of Serbia
- Kosta Popović, Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Republic of Serbia
- Dušica Popović, Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Republic of Serbia
- HPLC method validation for the quantification of lomustine to study pharmacokinetics of thermosensitive liposome-encapsulated lomustine containing iohexol for CT imaging in C6 glioma rats
Abstract To study the pharmacokinetics of the novel lomustine liposome, a specific, simple, and reliable high-performance liquid chromatography with ultraviolet detection (HPLC/UV) method for quantification of lomustine in rat plasma was established and validated. The calibration curve was linear over the concentration range of 0.05–5 μg/mL with the linearity ( r 2 ) being ≥0.9994. The intra- and inter-day precision was less than 5.87 and 10.47%, respectively, and the accuracy was within ±7.95%. The validated method has been successfully applied to a pharmacokinetic study of thermosensitive liposome-encapsulated lomustine containing iohexol and lomustine solution after intravenous administration to C6 glioma rats. Population pharmacokinetic (PPK) analysis was performed using NONMEM program for the plasma concentration versus time data. A one-compartment model with first-order elimination was established and proved to be the best description of the lomustine profile. Bootstrap analysis ( n = 1,000) was executed to evaluate the stability and robustness of the model. The pharmacokinetic parameters of lomustine liposome containing iohexol and lomustine solution in rats were simulated using the final PPK model: t 1/2 , AUC 0–∞ , C max were 0.28 ± 0.12, 0.19 ± 0.08, and 0.30 ± 0.13 h; 2.37 ± 0.76, 1.32 ± 0.42, and 0.90 ± 0.29 mg h/L; 5.15 ± 2.22, 3.91 ± 1.90, and 1.87 ± 0.35 μg/mL for heated, non-heated, and control group, respectively. The result indicated that thermosensitive liposome-encapsulated lomustine containing iohexol for CT imaging had different pharmacokinetic characteristics than lomustine solution. Compared with non-heated group, the bioavailability of lomustine was obviously increased in C6 glioma rat plasma.
- Content Type Journal Article
- Pages 1-9
- DOI 10.1007/s13318-011-0030-4
- Authors
- Luning Zhuang, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072 China
- Jing Gao, Tianjin State Key Laboratory of Pharmacokinetics and Pharmacodynamics, Tianjin Institute of Pharmaceutical Research, Tianjin, 300193 China
- Yong Zeng, Tianjin State Key Laboratory of Pharmacokinetics and Pharmacodynamics, Tianjin Institute of Pharmaceutical Research, Tianjin, 300193 China
- Fei Yu, School of Chemical Engineering and Technology, Tianjin University, Tianjin, 300072 China
- Bingjie Zhang, Tianjin First Center Hospital, Tianjin, 300192 China
- Mu Li, Tianjin First Center Hospital, Tianjin, 300192 China
- Hartmut Derendorf, Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA
- Changxiao Liu, Tianjin State Key Laboratory of Pharmacokinetics and Pharmacodynamics, Tianjin Institute of Pharmaceutical Research, Tianjin, 300193 China
- Intravenous prediction of human pharmacokinetic parameters for ketorolac, a non-steroidal anti-inflammatory agent, using allometry approach
Abstract The intravenous pharmacokinetics data of ketorolac in mice, rats, rabbits, dogs and monkeys were assembled from literature. The relationship between the main pharmacokinetic parameters [viz., volume of distribution ( V d ) and clearance (CL)] and body weight was studied across five mammalian species, using double-logarithmic plots to predict the human pharmacokinetic parameters of CL and V d using simple allometry or with correction factors [maximum life span potential (MLP), brain weight, CF1 (bile flow/liver weight) and CF2 (bile flow/body weight)]. The metabolism pattern, biotransformation pathways and the predominant urinary excretion of parent and the formed metabolites of ketorolac were found to be similar amongst mice, rats, rabbits, dogs, monkeys and humans, facilitating the scaling process. The human parameter value for V d was predicted by simple allometric equation: 0.2481W 1.0549 ( r 2 = 0.9217). The predicted V d value (21.92 L) is close to the reported value (17.5 L), whereas the CL was predicted by simple allometric approach or with standard correction factors viz., MLP, brain weight, CF1 and CF2. Best proximity CL value was obtained with MLP having allometric equation: 0.7126W 1.3264 ( r 2 = 0.9640). The outcome of this exercise suggests that allometric scaling with suitable correction factors could potentially be used to predict the human pharmacokinetic parameters of drugs belonging to non-steroidal anti-inflammatory drugs retrospectively.
- Content Type Journal Article
- Pages 1-7
- DOI 10.1007/s13318-011-0029-x
- Authors
- Ravindranath Reddy Gilibili, Drug Metabolism and Pharmacokinetics, Jubilant Biosys Ltd, Industrial Suburb, Yeshwanthpur, Bangalore, 560 022 India
- Ramesh Mullangi, Drug Metabolism and Pharmacokinetics, Jubilant Biosys Ltd, Industrial Suburb, Yeshwanthpur, Bangalore, 560 022 India
- Nuggehally R. Srinivas, Vanthys Pharmaceutical Development (Pvt) Ltd, Phoenix Pinnacle, Ulsoor Road, Bangalore, 560 001 India
- One-compartmental biometric blood loss calculation after cesarean section
Abstract Blood loss during cesarean section was calculated based on post-operative decrement of hemoglobin (Hb) and hematocrit (Hct) level. The model used for pregnant women was previously validated for non-pregnant women who underwent gynecological surgery. 1,068 pregnant women who underwent cesarean section and 517 women who underwent gynecological surgery were included in the study. Regression lines between collected ( x ) and calculated ( y ) blood loss in pregnant women ( y = 0.164 + 0.602 x ) and non-pregnant ( y = 0.255 + 0.750 x ) women were statistically parallel. This study confirmed the applicability of one-compartmental model based on the drop in Hb levels for blood loss calculations for both gynecological surgery and cesarean section. Improved methods for calculating blood loss, V after cesarean section as V = [0.0115 × body weight (kg) × ln (preoperative Hb/postoperative Hb)] + [0.1905 × height 3 (m) × ln (preoperative Hb/postoperative Hb)] + 0.3158 and after gynecological surgery V = [0.004 × body weight (kg) × ln (preoperative Hb/postoperative Hb)] + [0.4624 × height 3 (m) × ln (preoperative Hb/postoperative Hb)] + 0.0472 were suggested.
- Content Type Journal Article
- Pages 1-6
- DOI 10.1007/s13318-011-0042-0
- Authors
- Natasa Milosevic, Department of Farmacy, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, Novi Sad, Republic of Serbia
- Jovan Popovic, Department of Farmacy, Faculty of Medicine, University of Novi Sad, Hajduk Veljkova 3, Novi Sad, Republic of Serbia
- Zorica Grujic, Department of Obstetrics and Gynecology, Clinical Centre of Vojvodina, Novi Sad, Republic of Serbia
- Milan Rapaic, Computing and Control Department, Faculty of Technical Science, University of Novi Sad, Novi Sad, Republic of Serbia
- Preclinical pharmacokinetics and pharmacodynamics of apixaban, a potent and selective factor Xa inhibitor
Abstract Apixaban is a potent, highly selective, reversible, oral, direct factor Xa (fXa) inhibitor in development for thrombosis prevention and treatment. The preclinical pharmacokinetic (PK) attributes of apixaban feature small volume of distribution (Vd), low systemic clearance (CL), and good oral bioavailability. Apixaban is well absorbed in rat, dog, and chimpanzee, with absolute oral bioavailability of approximately 50% or greater. The steady-state Vd of apixaban is approximately 0.5, 0.2, and 0.17 l/kg in rats, dogs, and chimpanzees, while CL is approximately 0.9, 0.04, and 0.018 l/h/kg, respectively. In vitro metabolic clearance of apixaban is also low. Renal clearance comprises approximately 10–30% of systemic clearance in rat, dog, and chimpanzee. Anti-fXa activity, prothrombin time (PT), and HEPTEST ® clotting time (HCT) prolongation correlated well with plasma apixaban concentration in rat, dog and chimpanzee. There was no lag time between apixaban plasma concentration and the pharmacodynamic (PD) markers, suggesting a rapid onset of action of apixaban. The PK/PD analyses were performed using an inhibitory E max model for anti-fXa assay and a linear model for PT and HCT assays. The IC 50 values for anti-fXa activity were 0.73 ± 0.03 and 1.5 ± 0.15 μM for rat and dog, respectively. The apparent K i values for PT were approximately 1.7, 6.6, and 4.8 μM for rat, dog and chimpanzee, respectively. The apparent K i for HCT was approximately 1.3 μM for dog. Apixaban exhibits desirable PK and PD properties for clinical development with good oral bioavailability, small Vd, low CL, and direct, predictable, concentration-dependent PD responses.
- Content Type Journal Article
- Pages 1-11
- DOI 10.1007/s13318-011-0037-x
- Authors
- Kan He, Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, NJ, USA
- Joseph M. Luettgen, Discovery Biology, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ 08543, USA
- Donglu Zhang, Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, NJ, USA
- Bing He, Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, NJ, USA
- James E. Grace, Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, NJ, USA
- Baomin Xin, Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, NJ, USA
- Donald J. P. Pinto, Discovery Chemistry, Bristol-Myers Squibb Company, Princeton, NJ, USA
- Pancras C. Wong, Discovery Biology, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ 08543, USA
- Robert M. Knabb, Discovery Biology, Bristol-Myers Squibb Company, P.O. Box 4000, Princeton, NJ 08543, USA
- Patrick Y. S. Lam, Discovery Chemistry, Bristol-Myers Squibb Company, Princeton, NJ, USA
- Ruth R. Wexler, Discovery Chemistry, Bristol-Myers Squibb Company, Princeton, NJ, USA
- Scott J. Grossman, Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Company, Princeton, NJ, USA
No Issue Number - Comparison of the pharmacokinetics of sulfamethoxazole in native Han and Tibetan male Chinese volunteers living at high altitude
Abstract The aim of this study was to investigate the pharmacokinetics of sulfamethoxazole in native Han and Tibetan healthy Chinese subjects living chronically at high altitude. An open-labeled, controlled, prospective study was conducted in healthy Chinese male volunteers. Sulfamethoxazole 1,200 mg was administered orally to two groups: native Han and Tibetan volunteers living at high altitude (2,500–3,900 m [8,200–12,800 ft]). Blood samples were collected from an indwelling venous catheter into heparinized tubes before (baseline) study drug administration and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 36, and 48 h after study drug administration. Sulfamethoxazole in whole blood, plasma, and plasma water, and metabolite N 4 -acetyl-sulfamethoxazole in plasma were determined by HPLC. Tolerability was determined using blood chemistry testing, continuous 12-lead electrocardiogram, and blood pressure monitoring. The protein binding was significantly higher in the native Tibetan group (70.5 %) compared to the native Han group (67.3 %) ( p < 0.05). The binding of sulfamethoxazole to red blood cells was 7.4 and 8.3 % in the native Han and native Tibetan groups, respectively. There was no significant difference between the two groups. The AUC 0–∞ was significantly lower in the native Tibetan group compared to the native Han group ( p < 0.05), and other pharmacokinetics parameters were found to have no significant difference between the two groups. This study found little changes in the disposition of sulfamethoxazole in these native healthy Tibetan Chinese subjects living at high altitude in comparison to native healthy Han Chinese subjects living at high altitude.
- Permeation and metabolism of cocaine in the nasal mucosa
Abstract The rapid onset of psychostimulatory effects of cocaine following intranasal administration suggests either extremely rapid absorption into the bloodstream or the potential for cocaine’s access to the suggested direct nose-to-brain transport pathway. Cocaine transport was measured across excised bovine olfactory and respiratory mucosa to investigate site-specific uptake of cocaine. Flux in both the mucosal-to-submucosal ( J m–s ) and submucosal-to-mucosal ( J s–m ) directions across normal, 2, 4-dinitrophenol (2, 4-DNP) exposed, and de-epithelialized tissues increased linearly with increasing cocaine concentration, and no significant differences ( p < 0.05) in directional permeability were observed for each condition. Some metabolism of cocaine to benzoylecgonine was observed, both in full-thickness and de-epithelialized tissues, demonstrating the activity of the submucosal tissues, in addition to the epithelial cell layer, in determining the disposition of cocaine. Results indicate that cocaine is transported across the nasal mucosa predominantly via passive diffusion, and no significant differences were observed between transport behaviors in the olfactory and nasal respiratory tissues.
- Effect of fullerenol C<sub class="a-plus-plus">60</sub>(OH)<sub class="a-plus-plus">24</sub> on lipid peroxidation of kidneys, testes and lungs in rats treated with doxorubicine
Abstract The aim of this study is to investigate the protective effect of fullerenol C 60 (OH) 24 in various doses, on lipid peroxidation of rat’s kidneys, testes and lungs after application of doxorubicin. The experiment was performed on healthy male Wistar rats. The animals were randomly divided into five experimental groups and treated with saline (0.9 % NaCl i.v.), doxorubicin alone (10 mg/kg i.v.), combination of doxorubicin/fullerenol (50 and 100 mg/kg fullerenol, respectively, 30 min before the introduction of doxorubicin) and fullerenol alone (100 mg/kg), respectively. Animals were killed on the 2nd and 14th day after treatment. Products of lipid peroxidation and thiobarbituric acid are determined spectrophotometrically from the crude homogenate fraction of the kidney, testis and lung tissues of the rats. Fullerenol, applied as a pre-treatment of doxorubicin, significantly reduced or completely prevented the appearance of doxorubicin toxicity in kidneys and testes, in both tested doses. A dose of 100 mg/kg i.p. exhibited a better protective effect. When fullerenol was applied alone, at a dose of 100 mg/kg i.p, it did not significantly affect the intensity of lipid peroxidation in all tested organs.
- Pharmacokinetics of lansoprazole and its main metabolites after single and multiple intravenous doses in healthy Chinese subjects
Abstract The aim of the study was to evaluate and compare the pharmacokinetics of lansoprazole (LPZ) and its main metabolites, 5′-hydroxy lansoprazole (HLPZ) and lansoprazole sulfone (LPZS), after single and multiple intravenous (i.v.) doses of LPZ in healthy Chinese subjects. Twelve subjects (six males and six females) were given a single dose of LPZ by i.v. infusion on day 1, and multiple doses from day 2 to day 6. Blood samples were collected at designated time points for analysis of plasma concentrations of LPZ, HLPZ and LPZS by an LC–MS/MS method. LPZ was generally well tolerated in healthy Chinese subjects. After single and multiple i.v. doses of 30 mg LPZ, the C max values of LPZ, HLPZ and LPZS were 1490 ± 290 and 1450 ± 280, 175 ± 71 and 154 ± 56, and 51.3 ± 82.9 and 74.1 ± 158.7 ng/mL, with the AUC 0– t values 3280 ± 2550 and 4260 ± 3880, 381 ± 128 and 389 ± 111, and 389 ± 1204 and 700 ± 2255 ng h/mL, respectively. The t 1/2 and CL values of LPZ after single and multiple i.v. doses were 1.48 ± 1.03 and 2.19 ± 1.03 h, and 11.67 ± 4.49 and 9.56 ± 4.08 L/h, respectively. Compared with the pharmacokinetics of LPZ after a single dose, t 1/2 increased markedly, CL decreased significantly and AUC increased by over 20 % after multiple doses. The results indicated that there was drug accumulation of LPZ after multiple i.v. doses, and there was no gender-related difference in pharmacokinetics of LPZ and its two metabolites.
No Issue Number - Pharmacokinetic and tolerability profile of pridopidine in healthy-volunteer poor and extensive CYP2D6 metabolizers, following single and multiple dosing
Abstract Pridopidine is being developed for the treatment of impaired motor function associated with Huntington’s disease and belongs to a new class of compounds known as dopidines, which act as dopaminergic stabilizers. In vitro studies have shown that pridopidine is a substrate for the P450 cytochrome 2D6 enzyme (CYP2D6), and clinical data show that the half-life of pridopidine is different following single dosing versus at steady state. To further investigate the pharmacokinetic profile of pridopidine and to establish whether dose adjustment is needed in poor CYP2D6 metabolizers, a single-centre, open-label, multiple-dose study in healthy volunteers was performed. In total, 24 extensive CYP2D6 metabolizers (EMs) and 12 poor CYP2D6 metabolizers (PMs) were enrolled. Both groups received 45 mg pridopidine twice daily (b.i.d.). Plasma samples were taken during the first day of b.i.d. dosing (Day 1) and at steady state, following 14 days of b.i.d. dosing. At Day 1, total exposure in PMs was almost three times higher than those in EMs (AUC 0–∞ = 11,192 and 3,782 h·ng/mL, respectively; PM/EM ratio = 2.96; p < 0.001). However, at steady state, PMs and EMs had comparable exposure due to a reduction in pridopidine elimination in EMs over time. Thus, at steady-state peak ( C max ) and total (AUC 0–24 ) exposures were only 1.24 and 1.29 times higher, respectively, in PMs than EMs. These results support that pridopidine is a CYP2D6 auto-inhibitor. Pridopidine was well tolerated in both EMs and PMs. The slightly higher exposure level in PMs at steady state does not indicate a need for dose adjustment or genotyping for CYP2D6 metabolizer status.
- Analysis of thiopurine <em class="a-plus-plus">S</em>-methyltransferase phenotype–genotype in a Tunisian population with Crohn’s disease
Abstract This study was conducted to investigate the thiopurine S -methyltransferase TPMT activity distribution and gene mutations in Tunisian population with positive diagnostic for Crohn’s disease. TPMT activity was measured in Tunisian population ( n = 88) by a high performance liquid chromatography assay. Polymerase chain reaction-based methods were used to determine the frequency of TPMT mutant alleles TPMT*2, TPMT*3A, TPMT*3B and TPMT*3C. TPMT activity was normally distributed, ranging from 4.58 to 35.27 nmol/(h ml) RBC with a mean of 18.67 ± 7.10 nmol/(h ml) RBC. Seven TPMT*3A heterozygotes and one TPMT*3C homozygote were found in 88 patients, with allele frequencies of 0.039 and 1.13, respectively. TPMT*3A and the TPMT*3C, which cause the largest decrease in enzyme activity, were both variant alleles detected in the Tunisian population.
- Pharmacokinetic analysis of doxifluridine and its metabolites, 5-fluorouracil and 5-fluorouridine, after oral administration in beagle dogs
Abstract Doxifluridine (5′-deoxy-5-fluorouridine, 5′-dFUR) is a fluoropyrimidine derivative that is activated preferentially in malignant cells by thymidine phosphorylase to form 5-fluorouracil (5-FU). The purpose of this study was to investigate the pharmacokinetic properties of doxifluridine and its two major metabolites, 5-FU, and 5-fluorouridine (5-FUrd), in beagle dogs following a single oral administration of 200 mg doxifluridine capsule (Furtulon ® ). After the administration of 200 mg of Furtulon to 23 beagle dogs, the plasma concentrations of doxifluridine, 5-FU, and 5-FUrd were measured simultaneously, using LC–MS/MS. The parent–metabolite compartment model with first-order absorption and Michaelis–Menten kinetics described the pharmacokinetics of doxifluridine, 5-FU, and 5-FUrd. Michaelis–Menten kinetics sufficiently explained the generation and elimination processes of 5-FU and 5-FUrd. The studies described here are the first to evaluate the relationship between pharmacokinetics of doxifluridine and its metabolites in dogs, and these findings will help in understanding the toxicity mechanism of doxifluridine.
- Disposition of ceftriaxone in hepatopathic goats following single-intramuscular dosing
Abstract Hepatopathy sometimes may interfere with metabolism and/or elimination of drugs which undergo major hepatic clearance. Twelve healthy goats were equally divided into two groups (I and II) and hepatopathy was induced by carbontetrachloride in the second group (group II). A single dose of ceftriaxone at 50 mg/kg was administered to each group intramuscularly. Disposition of ceftriaxone in plasma of healthy goats showed a typical absorption–reabsorption phase. However, the reabsorption phase was totally absent in hepatopathic goats and the disposition of ceftriaxone showed only absorption and distribution/elimination phase. The drug persisted in plasma for 6 h in hepatopathic animals, whereas the drug can only be detected up to 2 h in healthy animals indicating longer persistence of ceftriaxone in the former group. Ceftizoxime, the active metabolite of ceftriaxone was available in urine of group I animals, whereas only ceftriaxone was detected in the urine of hepatopathic animals suggesting impairment of metabolism of the parent drug in hepatopathy. Therefore, the reabsorption and metabolism of ceftriaxone in goats should be taken into consideration for drug monitoring.
- Contribution of rat intestinal metabolism to the xenobiotics clearance
Abstract Michaelis–Menten constants K m and V max values were determined by product formation and substrate depletion at several substrate concentrations of 4-methylumbelliferone using rat intestinal microsomes. K m and V max values determined by measuring product formation were in good agreement with substrate depletion approach. We also investigated hepatic and intestinal in vitro intrinsic clearance (CL int ) in the liver and intestinal microsomes and compare with reports in the literature using nine test compounds, atorvastatin, 7-ethoxycoumarin, indomethacin, 4-methylumbelliferone, midazolam, nifedipine, testosterone, terfenadine and verapamil, in rats. CL int was determined from the substrate disappearance rate at 0.1 and 0.5 μM in the rat intestinal and liver microsomes, respectively. These results showed that both the liver and the intestine contributed to the metabolism of these compounds. The intestinal intrinsic clearance values of all these drugs, except for terfenadine in the rat intestinal microsomes, were lower than their hepatic intrinsic clearance per milligram protein, showing that there was an organ difference in metabolism between the liver and intestinal. These results make the evaluation using the intestinal more useful and provide a basis for predicting clearance using intestinal.
- Effective concentration-based serum pharmacodynamics for antifungal azoles in a murine model of disseminated <em class="a-plus-plus">Candida albicans</em> infection
Abstract An assessment of the effective in vivo concentrations of antifungal drugs is important in determining their pharmacodynamics, and therefore, their optimal dosage regimen. Here we establish the effective in vivo concentration-based pharmacodynamics of three azole antifungal drugs (fluconazole, itraconazole, and ketoconazole) in a murine model of disseminated Candida albicans infection. A key feature of this study was the use of a measure of mycelial ( m ) growth rather than of yeast growth, and pooled mouse sera rather than synthetic media as a growth medium, for determining the minimum inhibitory concentrations (MICs) of azoles for C. albicans (denoted serum mMICs). The serum mMIC assay was then used to measure antifungal concentrations and effects as serum antifungal titers in the serum of treated mice. Both serum mMIC and sub-mMIC values reflected the effective in vivo serum concentrations. Supra-mMIC and mMIC effects exhibited equivalent efficacies and were concentration-independent, while the sub-mMIC effect was concentration-dependent. Following administration of the minimum drug dosage that inhibited an increase in mouse kidney fungal burden, the duration periods of these effects were similar for all drugs tested. The average duration of either the mMIC effect including the supra-mMIC effect, the sub-mMIC effect, or the post-antifungal effect (PAFE) were 6.9, 6.5 and 10.6 h, respectively. Our study suggests that the area under the curve for serum drug concentration versus time, between the serum mMIC and the sub-mMIC, and exposure time above the serum sub-mMIC after the mMIC effect, are major pharmacodynamic parameters. These findings have important implications for effective concentration-based pharmacodynamics of fungal infections treated with azoles.
- The impact of pregnancy on urinary ketorolac metabolites after single intravenous bolus
Abstract Compared to female volunteers or postpartum, ketorolac clearance is higher at delivery. To explore the alterations that explain this higher clearance, urinary ketorolac metabolites collected at delivery ( n = 40) were compared to female volunteers (unpaired, n = 8) or postpartum (paired, n = 8) following intravenous administration of 30 mg ketorolac tromethamine. A mean 38 (SD 9) % of the ketorolac dose was retrieved in 8-h urine collections. This was based on mean portions of 56 (20), 10 (14) and 33 (12) % for free ketorolac, ketorolac-glucuronide and p -hydroxy-ketorolac, respectively. The mean ketorolac-glucuronide portion at delivery (5 %) was lower compared to female volunteers (21 %) or postpartum (21 %) ( p = 0.003 and p = 0.002, respectively). Similarly, there was a difference in mean portion of free urinary ketorolac at delivery when compared to healthy female volunteers (60–45 %, p = 0.046). Using paired statistics, the mean portion of total urinary ketorolac was lower (62–73 %, p = 0.015) while the portion retrieved as p -hydroxy-ketorolac was significantly higher at delivery compared to postpartum (38–28 %, p = 0.031). The differences in urine metabolites suggest that the increased ketorolac clearance at delivery is in part explained by increased metabolic clearance to p -hydroxy-ketorolac, reflecting increased oxidation activity.
- Determination of phillygenin in rat plasma by high-performance liquid chromatography and its application to pharmacokinetic studies
Abstract The research group has been dedicated to the study of Fructus Forsythiae which was used widely in traditional Chinese medicines. And some research results have been accepted in Chinese Pharmacopeia. In a recent study, phillygenin was found to be a potential “metabolite” of phillyrin and the effective material of phillyrin may be changed according to the in vivo pharmacokinetic process. Therefore, a sensitive, specific, accurate, and reproducible reversed phase HPLC method for the determination of phillygenin in rat plasma was developed. Separation was achieved on a Hypersil ODS C 18 column with UV detection at 277 nm. The good linear calibration curves ranged from 0.039 to 20 μg/mL with the limit of quantification estimated as 0.026 μg/mL. The intra- and inter-day precisions were in the range of 98–103 %. The average recoveries of phillygenin were 90.54, 92.47, and 92.15 % for phillygenin of 0.156, 1.25, and 10.0 μg/mL. And the Ruggedness of HPLC method was evaluated. The analytical method was also successfully applied to the pharmacokinetic study of phillygenin in rat for the first time. A rapid distribution was observed from the plasma concentration–time curves, and was followed by a quick elimination for phillygenin. The mean t 1/2z was 6.02, 5.62, and 5.79 min for 1.4, 2.8, and 5.6 mg/kg, respectively. The AUC (0–t) increased linearly from 166.29 to 332.48 mg/L min. All results indicated that, in the range of the doses examined, the pharmacokinetics of phillygenin in rat was based on first-order kinetics.
- Effect of ketoprofen and indomethacin on methotrexate pharmacokinetics in mice plasma and tumor tissues
Abstract Methotrexate (MTX) has been used in combination with nonsteroidal anti-inflammatory drugs in the treatment of inflammatory diseases as well as malignancies. Severe adverse effects with this combination may occur, usually resulting from inhibition of renal transporters. Solid Ehrlich Carcinoma was experimentally induced by implantation of Ehrlich Ascites Carcinoma cells subcutaneously into the thigh of mice, and after 30 days, mice were divided into three groups: Group I that served as control group received MTX (50 mg/kg, i.p.); Group II received ketoprofen (100 mg/kg, i.p.) and then after half an hour received MTX (50 mg/kg, i.p.); Group III received indomethacin (10 mg/kg, i.p.) and then after half an hour received MTX (50 mg/kg, i.p.). Plasma and tissue samples were collected at different time points and then MTX concentrations were determined by HPLC. The injection of ketoprofen or indomethacin before MTX injection resulted in significant increase in the AUC and CP max of MTX ( p < 0.05) and significant decrease in CL/F and Vd/F of MTX ( p < 0.05) in mice plasma. The effects were more significant after injection of indomethacin than in case of ketoprofen. The study showed that administration of ketoprofen or indomethacin prior to MTX caused significant decrease in MTX elimination and significant increase in MTX extent of absorption which may lead to severe adverse effects if coadministered in human.
- Individualization of a pharmacokinetic model by fractional and nonlinear fit improvement
<h3 class="a-plus-plus">Abstract</h3> <p class="a-plus-plus">This study presents application of a new linear and nonlinear fractional derivative two compartmental model to the evaluation of individual pharmacokinetics. In the model, the integer order derivatives are replaced by derivatives of real order. A specific nonlinear function is used for the fit improvement of a fractional derivative two compartmental model with the mass balance conservation. The agreement of the values predicted by the proposed model with the values obtained through experiments with bumetanide tablets in human volunteers is shown to be good. Thus, pharmacokinetics of bumetanide can be described well by a linear or a nonlinear two compartmental model with fractional derivatives of the same order proposed here. Parameters in the model are determined by the least squares method and the particle swarm optimization numerical procedure is used. The results show that the linear fractional order two compartmental model for bumetanide is useful improvement of the classical (integer order) two compartmental model and that the nonlinear fractional order model is useful improvement of the linear model in a great number of volunteers.</p>
- Deleterious nonsynonymous single nucleotide polymorphisms in human solute carriers: the first comparison of three prediction methods
Abstract Abundant nsSNPs have been found in genes coding for human solute carrier (SLC) transporters, but there is little known about the relationship between the genotype and phenotype of nsSNPs in these membrane proteins. It is unknown which prediction method is better suited for the prediction of nonneutral nsSNPs of SLC transporters. We have identified 2,958 validated nsSNPs in human SLC family members 1–47 from the Ensembl genome database and the NCBI SNP database. Using three different algorithms, 37–45 % of nsSNPs in SLC genes were predicted to have functional impacts on transporter function. Predictions largely agreed with the available experimental annotations. Overall, 76.5, 74.4, and 73.5 % of nonneutral nsSNPs were predicted correctly as damaging by SNAP, SIFT, and PolyPhen, respectively, while 67.4, 66.3, and 76.7 % of neutral nsSNPs were predicted correctly as nondamaging by the three methods, respectively. This study identified many amino acids that were likely to be functionally critical but have not yet been studied experimentally. There was a significant concordance between the predicted results of different methods. Evolutionarily nonneutral (destabilizing) amino acid substitutions are predicted to be the basis for the pathogenic alteration of SLC transporter activity that is associated with disease susceptibility and altered drug/xenobiotic response.
- Effects of pyridoxine on the intestinal absorption and pharmacokinetics of isoniazid in rats
Abstract Pyridoxine is always simultaneously administered orally with isoniazid for tuberculosis patients in the clinic to prevent or treat the nervous system side effects induced by isoniazid. So the aim of this research was to investigate the effects of pyridoxine on the intestinal absorption and pharmacokinetics of isoniazid. The intestinal absorption of isoniazid with or without pyridoxine was investigated by the rat single-pass intestinal perfusion model in situ, and a high-performance liquid chromatographic method was applied to study the pharmacokinetics of isoniazid with or without pyridoxine. The results suggested that the intestinal apparent permeability ( P app ) and intestinal absorption rate constant ( K a ) for isoniazid (30 μg/ml) were decreased by 43.7 and 36.4 %, respectively, by co-perfused pyridoxine (40 μg/ml). In vivo, the effect of pyridoxine on isoniazid pharmacokinetic correlated with the doses of pyridoxine. The blood concentrations of isoniazid at the absorption phase were affected by co-administered pyridoxine, but the AUC and C max of isoniazid were not greatly affected by pyridoxine as expected from the inhibition by pyridoxine of the intestinal absorption of isoniazid, which could be caused by its rapid absorption phase. Therefore, although the intestinal absorption of isoniazid could be significantly inhibited by pyridoxine, the pharmacokinetics of isoniazid oral administration was not greatly affected by the decreased intestinal absorption of isoniazid due to its rapid absorption.
- Genome-wide association study reveals a complex genetic architecture underpinning-induced CYP3A4 enzyme activity
Abstract Atypical cytochrome P450 3A4 (CYP3A4) enzyme activity—induced and inhibited—is thought to be the driver of numerous poor or adverse therapeutic responses to up to 50 % of all commonly prescribed drugs. We carried out a genome-wide association study to identify common genetic variants associated with variation in induced CYP3A4 activity. A total of 310 twins were included in this study. Each participant had already completed a 14 days course of St John’s Wort to induce CYP3A4, which was quantified through the metabolic ratio of exogenous 3-hydroxyquinine to quinine. We failed to detect any genome-wide significant associations ( P < 1 × 10 −8 ) with variation in induced CYP3A4 activity although several genomic regions were highlighted which may play minor roles. We report the first GWAS of variation in induced CYP3A4 activity and our preliminary results indicate a complex genetic architecture underpinning induced CYP3A4 enzyme activity.
- Impact of physiochemical properties on pharmacokinetics of protein therapeutics
<h3 class="a-plus-plus">Abstract</h3> <p class="a-plus-plus">Physicochemical properties, such as molecular weight, size, partition coefficient, acid dissociation constant and solubility have a great impact on pharmacokinetics of traditional small molecule drugs and substantially used in development of small drugs. However, predicting pharmacokinetic fate (absorption, distribution, metabolism and elimination) of protein therapeutics from their physicochemical parameters is extremely difficult due to the macromolecular nature of therapeutic proteins and peptides. Their structural complexity and immunogenicity are other contributing factors that determine their biological fate. Therefore, to develop generalized strategies concerning development of therapeutic proteins and peptides are highly challenging. However, reviewing the literature, authors found that physiochemical properties, such as molecular weight, charge and structural modification are having great impact on pharmacokinetics of protein therapeutics and an attempt is made to provide the major findings in this manuscript. This manuscript will serve to provide some bases for developing protein therapeutics with desired pharmacokinetic profile.</p>
- Effect of borneol on cytochrome P450 3A enzyme and midazolam pharmacokinetics in rats
Abstract Borneol is a commonly used herbal medication in China and Japan. Previous studies have indicated that borneol could reduce the plasma concentrations of oneself and concomitant drugs, and its first-pass metabolism could be catalyzed by the cytochrome P450 3A (CYP3A) enzyme as well. The impact of borneol on CYP3A activity and efficacy in influencing the pharmacokinetics of co-administrated drugs is currently unknown. Therefore, the purpose of the current study is to investigate the effect of borneol on CYP3A enzyme in vivo. After treatment with borneol twice daily for 3 days, rat liver microsomes were exposed to probe substrates to determine CYP3A enzyme activity, protein, and RNA harvested using microsomal testosterone 6β-hydroxylation as a marker of enzyme activity. To verify the result, the effect of borneol on the pharmacokinetics of the CYP3A model substrate midazolam was further examined. The results showed that borneol treatment had increased CYP3A expression at the mRNA, protein, and activity (testosterone 6β hydroxylase activity) level in rat liver microsomes. In addition, borneol accelerated the metabolism of midazolam, which was consistent with the enhancement in CYP3A metabolic capacity. The hepatic clearance (Cl) of midazolam injected via the caudal vein in rats following borneol co-administration was higher; however, the area under the curve (AUC 0–∞ ) was lower than the solvent. Hence, it was proposed that borneol could increase the metabolic activity of the CYP3A enzyme, which might cause drug–drug interactions in humans when using Chinese herbal or Western medicine with borneol.
- Effect of natural borneol on the pharmacokinetics and distribution of nimodipine in mice
Abstract The purpose of this study was to investigate the effect of natural borneol (NB) on the pharmacokinetics and distribution of nimodipine in mice. A single dose of nimodipine was administered intravenously (2 mg/kg) to mice pretreated with NB (250 mg/kg) or vehicle. Blood as well as brain, liver, and kidney tissue samples were collected at 5, 10, 20, 40, and 60 min post-dose nimodipine. The concentrations of nimodipine in plasma and tissues were determined by ultra performance liquid chromatography (UPLC) coupled with UV detection, and the pharmacokinetic parameters were calculated based on non-compartmental analysis. NB increased the plasma AUC 5–60 min by 26 % compared to the vehicle. In addition, brain concentrations of nimodipine in NB-treated mice were significantly higher than those in control mice with the increased AUC 5–60 min by 30 %. In liver and kidney, NB also caused 26 and 47 % increase in AUC 5–60 min , respectively. These results implicated that NB may inhibit the metabolism or elimination of nimodipine and enhance its distribution in brain and kidney tissue.
- Is pomegranate juice a potential perpetrator of clinical drug–drug interactions' Review of the in vitro, preclinical and clinical evidence
Abstract The area of fruit juice–drug interaction has received wide attention with numerous scientific and clinical investigations performed and reported for scores of drugs metabolized by CYP3A4/CYP2C9. While grapefruit juice has been extensively studied with respect to its drug–drug interaction potential, numerous other fruit juices such as cranberry juice, orange juice, grape juice, pineapple juice and pomegranate juice have also been investigated for its potential to show drug–drug interaction of any clinical relevance. This review focuses on establishing any relevance for clinical drug–drug interaction potential with pomegranate juice, which has been shown to produce therapeutic benefits over a wide range of disease areas. The review collates and evaluates relevant published in vitro, preclinical and clinical evidence of the potential of pomegranate juice to be a perpetrator in drug–drug interactions mediated by CYP3A4 and CYP2C9. In vitro and animal pharmacokinetic data support the possibility of CYP3A4/CYP2C9 inhibition by pomegranate juice; however, the human relevance for drug–drug interaction was not established based on the limited case studies.
- A clinical pharmacokinetic study comparing two azelastine hydrochloride nasal formulations in a single-dose design
Abstract Azelastine hydrochloride is a potent second-generation antihistamine, available in Europe and the USA as a nasal spray formulation for the treatment of allergic rhinitis symptoms. GlaxoSmithKline (GSK) Consumer Healthcare has developed a new nasal formulation of azelastine hydrochloride. The present study was aimed at comparing the clinical pharmacokinetic profiles and assessing the bioequivalence of the new formulation of azelastine hydrochloride with a marketed reference nasal spray product. This was a randomized, two-way crossover, two-stage, single-dose pharmacokinetic study with 2 weeks washout between the two treatment periods. A dosage of 0.28 mg of the test and reference products was administered as a single dose to healthy volunteers according to the crossover design. Twenty-three subjects (15 subjects from stage 1 and 8 subjects from stage 2) were enrolled in the study. Adjusted mean values for AUC 0– t were 1,526.8 h pg/mL for the test drug and 1,441.5 h pg/mL for the reference drug; for C max the values were 61.59 pg/mL for the test drug and 58.21 pg/mL for the reference drug. The 94.12 % CI of geometric mean ratios (test/reference) were 0.99–1.13 and 0.95–1.18 for AUC 0– t and C max . This met the predefined criteria for bioequivalence between test and reference drugs. Secondary pharmacokinetic parameters for azelastine and for the metabolite desmethyl azelastine, AUC (0–∞) and t max , were numerically similar between the two study treatments. Both test and reference azelastine hydrochloride formulations were well tolerated at single dose. This study demonstrated the bioequivalence between the new azelastine hydrochloride nasal spray formulation and the marketed reference Allergodil ® after single-dose administration.
- Increased elimination of paclitaxel by magnesium isoglycyrrhizinate in epithelial ovarian cancer patients treated with paclitaxel plus cisplatin: a pilot clinical study
Abstract Magnesium isoglycyrrhizinate (MI) has been complementarily used for restoring the hepatic impairments caused by taxol plus platinum based chemotherapies in China. Due to the hepatic dependence of paclitaxel elimination, this pilot clinical study aimed to investigate the influence of MI on the pharmacokinetics of paclitaxel in epithelial ovarian cancer patients. During the standard chemotherapy of intravenous paclitaxel (125 mg/m 2 infused over a 3-h period) and intraperitoneal cisplatin (60 mg/m 2 ) for patients with FIGO stage II epithelial ovarian cancer, 9 each of total 18 patients were respectively treated with intravenous MI (100 mg) or vehicle control for 4 days. Plasma paclitaxel was analyzed by HPLC and the pharmacokinetic parameters were calculated with non-compartmental analysis. The hematological, hepatic and renal status was monitored before and 3 days after paclitaxel administration. It was observed the terminal t 1/2 and MRT of paclitaxel were significantly ( p = 0.002 and 0.001) reduced by MI, respectively, from 11.0 ± 2.2 and 5.6 ± 1.0 h to 7.7 ± 1.7 and 4.0 ± 0.3 h. Hematological toxicity indicated by platelet count and hepatic events marked with ALT, AST and γ-GT were significant in both groups. In spite of the insignificance of decreased system exposure of paclitaxel and recovered hepatic function by MI, they did correlate with each other. It was therefore deduced that the liver toxicities of paclitaxel plus cisplatin chemotherapy potentially decrease hepatic elimination and increase system exposure of paclitaxel, and the recovery of liver function by MI helps to restore hepatic clearance of paclitaxel. The clinical significance of this pharmacokinetic interaction requires further studies with larger population size.
- Integration of preclinical and clinical knowledge to predict intravenous PK in human: Bilastine case study
Abstract Modern pharmacometrics can integrate and leverage all prior proprietary and public knowledge. Such methods can be used to scale across species or comparators, perform clinical trial simulation across alternative designs, confirm hypothesis and potentially reduce development burden, time and costs. Crucial yet typically lacking in integration is the pre-clinical stage. Prediction of PK in man, using in vitro and in vivo studies in different animal species, is increasingly well theorized but could still find wider application in drug development. The aim of the present work was to explore methods for bridging pharmacokinetic knowledge from animal species (i.v. and p.o.) and man (p.o.) into i.v. in man using the antihistamine drug bilastine as example. A model, predictive of i.v. PK in man, was developed on data from two pre-clinical species (rat and dog) and p.o. in man bilastine trials performed earlier. In the knowledge application stage, two different approaches were used to predict human plasma concentration after i.v. of bilastine: allometry (several scaling methods) and a semi-physiological method. Both approaches led to successful predictions of key i.v. PK parameters of bilastine in man. The predictive i.v. PK model was validated using later data from a clinical study of i.v. bilastine. Introduction of such knowledge in development permits proper leveraging of all emergent knowledge as well as quantification-based exploration of PK scenario, e.g. in special populations (pediatrics, renal insufficiency, comedication). In addition, the methods permit reduction or elimination and certainly optimization of learning trials, particularly those concerning alternative off-label administration routes.
- Pharmacokinetics, tissue distribution and excretion of manganese (III) meso-tetra [3-(2-(2-methoxy)-ethoxy) ethoxy] phenyl porphyrin chloride, a novel superoxide dismutase mimic, in Wistar rats
Abstract Manganese (III) 5, 10, 15, 20-tetrakis [3-(2-(2-methoxy)-ethoxy) ethoxy] phenyl porphyrin chloride, designated HSJ-0017, is a novel superoxide dismutase mimic. It exhibits strong free-radical scavenging activities in vitro and in vivo. The aim of the present study was to investigate the pharmacokinetics, tissue distribution and excretion of HSJ-0017 in Wistar rats following a single intravenous administration. Wistar rats were given different doses of HSJ-0017 by single intravenous injection. Biological samples of rats were collected and were assayed by the HPLC method. The pharmacokinetics, tissue distribution and excretion of HSJ-0017 were investigated. The pharmacokinetic data of HSJ-0017 in rats following intravenous injection was best-fit by a two-compartment model. T max of HSJ-0017 in plasma following intravenous injection was 0.083 h. AUC and plasma drug concentration were found to increase in a dose-related fashion. The highest concentrations of HSJ-0017 were detected in the liver (82.25 ± 13.99 μg/g) of rats, followed by the kidney, small intestine, lung, plasma, heart, spleen, and stomach within 2 h postdose. No HSJ-0017 was detected in the uterus, parorchis or brain of rats during the 24-h period of examination. The total cumulative excretion of HSJ-0017 in rat bile and urine were found to be 78.85 and 67.58 %, respectively. Our study has led to the view that the HSJ-0017 can be rapidly distributed to tissues after intravenous administration, but cannot diffuse through the blood–brain barrier. The faecal and biliary excretion of unchanged HSJ-0017 are the major routes of HSJ-0017 elimination.
- The impact of drug transporters on adverse drug reaction
Abstract In this review, we have highlighted the adverse drug reaction mediated by transporters from two aspects: (1) competitive interactions between drug and drug/metabolite/endogenous substance mediated by transporters; (2) the expression/function change of transporter due to physiologic factors, disease, and drugs induction. It indicated that transporters exhibited a broad substrate specificity with a degree of overlap, which could change the pharmacokinetics of drugs and cause toxicity due to competition interactions among substrates. In addition, the expression and function of transporters were regulated by physiological conditions, pathological conditions, and drugs induction, which could cause adverse drug reaction and interindividual differences. Furthermore, one substrate was always medicated by several transporters and often subjected to metabolism by CYP enzymes, so we should be more aware of the increased plasma concentration of drugs caused by drug transporters as well as drug metabolizing enzymes synergistically, especially for drugs with narrow therapeutic window. In addition, the weightiness for one transporter to induce drugs plasma/tissue concentration change could be different in different condition. On the whole, transporters were corresponding with systemic/organs exposure of drug/metabolites/endogenous compounds. So understanding the expression and function in drug transporters will result in better strategies for optimal dosage regimen and reduce the risk for drug adverse reaction as well as adverse drug–drug interactions.
- Pharmacokinetic study of multiple active constituents after oral gavage of Guizhi decoction in rats using a LC–MS/MS method
Abstract Guizhi decoction (GZD) is a classic traditional Chinese medicine formula, clinically used for the treatment of influenza, common cold, and other pyretic conditions. A sensitive, specific, and validated liquid chromatography–tandem mass spectrometric (LC–MS/MS) method was developed to investigate the pharmacokinetic properties of cinnamic acid, hippuric acid, paeoniflorin, and glycyrrhetic acid in rat. After single dose oral administration of 7.9 g extract/kg body weight GZD in rats, plasma concentrations of cinnamic acid, hippuric acid, paeoniflorin, and glycyrrhetic acid were measured by LC–MS/MS. Pharmacokinetic parameters were calculated from the plasma concentration–time data. The values of AUC 0−t , half-life ( t 1/2 ), and C max were 7.2 ± 2.3 μg h/mL, 1.2 ± 0.3 h, and 9.2 ± 5.2 μg/mL for cinnamic acid, 53 ± 31 μg h/mL, 2.8 ± 2.0 h, and 17 ± 3 μg/mL for hippuric acid, 1.1 ± 0.5 μg h/mL, 1.9 ± 1.1 h, and 0.6 ± 0.3 μg/mL for paeoniflorin, and 11 ± 6 μg h/mL, 6.6 ± 2.5 h, and 0.9 ± 0.6 μg/mL for glycyrrhetic acid, respectively. The results would offer useful information for effective components of GZD in vivo.
- Pharmacokinetic disposition of anagliptin, a novel dipeptidyl peptidase-4 inhibitor, in rats and dogs
Abstract The pharmacokinetic disposition of anagliptin, an orally active and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor was evaluated in male rats and dogs. Anagliptin was well absorbed in dogs (70.4 %) and moderately to well absorbed in rats ranging from 38.1 to 85.5 % depending on the dose. In situ testing indicated that anagliptin absorption from rat intestine was apparently limited by P-glycoprotein. The absorbed radioactivity was distributed rapidly throughout the body, and high levels of radioactivity were found in the tissues expressing DPP-4 at high levels, especially small intestine, kidney and liver. In both species, the major circulating component was unchanged anagliptin; major circulating metabolites were M1 resulting from hydrolysis of the cyano group and M6 and M7, both of which resulting from the oxidation-cleavage of the methylene function adjacent to the amine. After intravenous dosing, urinary excretion of radioactivity was the major route of elimination for rats (64.6 %) and dogs (66.2 %), and biliary excretion was demonstrated to be an important pathway in rats (25.2 %). The total recovery was good (97.5–99.5 %) and most of the radioactivity was excreted by 24 h in both species. The renal clearance of unbound anagliptin in rats (91.7 ml/min/kg) was much higher than the glomerular filtration rate, indicative of active renal elimination.
- Interactions between new quinolone antibacterials and diagnostic drug containing manganese
Abstract A diagnostic drug containing manganese chloride tetrahydrate as a major ingredient is available since 2006. It is used in magnetic resonance imaging as a negative contrast medium for magnetic resonance cholangiopancreatography of the gastrointestinal tract. However, there is no report regarding interaction between manganese and new quinolone antibacterials. We investigated the interactions between new quinolone antibacterials and a diagnostic drug containing manganese in vitro. We evaluated the rate of formation of chelate complex by reacting new quinolone antibacterials (levofloxacin, ofloxacin, ciprofloxacin) with a diagnostic drug containing manganese. The EC 50 values of the formation of chelate complex for levofloxacin, ofloxacin, and ciprofloxacin were 5.14 ± 0.14, 5.29 ± 0.14, and 0.96 ± 0.04 mM, respectively. The rates of formation of chelate complex by levofloxacin, ofloxacin, and ciprofloxacin in a reaction with the diagnostic drug were 17.0, 18.9, and 55.5 % in clinical condition, respectively. Our results suggest that a complex of each antibacterial and manganese was formed, with ciprofloxacin causing the strongest interaction. In addition, our findings indicate that the degree of interaction may be an important problem in clinical settings with concomitant administration of a new quinolone antibacterial and diagnostic drug containing manganese.
- Influence of the multidrug transporter P-glycoprotein on the intracellular pharmacokinetics of vandetanib
Abstract Efflux transporters play an important role in the resistance of tumor cells against anticancer agents. Interaction between these transporters, including P-glycoprotein (P-gp), and drugs might influence their pharmacological properties and toxicities. The aim of this study was to investigate whether vandetanib (Caprelsa ® ), a small tyrosine kinase inhibitor, could interact with the multidrug transporter P-gp. Interaction of vandetanib with the P-gp was investigated using the parental cell line (IGROV1) and the P-gp doxorubicin-resistant (IGROV1-DXR) cell line, derived from the parental drug-sensitive IGROV1 cells. Cytotoxicity tests were assessed in both cell lines to examine the impact of P-gp on the cell survival after a vandetanib treatment. The effects of P-gp on vandetanib intracellular pharmacokinetics were investigated. To this aim, we developed a quantitative liquid chromatography tandem mass spectrometry to quantify vandetanib in cell medium. Results showed that overexpression of P-gp confers resistance to vandetanib in the IGROV1-DXR cell line. Using a LC–MS/MS assay validated in cell medium, cellular pharmacokinetic studies revealed that in cells overexpressing the P-gp intracellular concentrations of vandetanib were decreased compared to parental cell line. For the first time, vandetanib is described as a substrate of P-gp. In tumor cells, P-gp could be responsible for cellular resistance to vandetanib. It may be relevant to the clinical efficacy of vandetanib. Moreover, interaction of vandetanib with P-gp could modify the pharmacodynamics of other conventional chemotherapeutics, substrates of P-gp. It could impact on the overall response to anticancer therapy.
- Genotype–phenotype correlation of cytochrome P450 2C9 polymorphism in Indian National Capital Region
Abstract Identification of polymorphism of cytochrome P450 2C9 (CYP2C9) enzymes in different ethnic populations is important to understand the differences in clinical responses to drugs. This study determines the CYP2C9 genetic polymorphism in Indian National Capital Region and correlates the phenotype–genotype. Losartan (25 mg) was administered to 107 volunteers to assess CYP2C9 activity, and, on the basis of results, volunteers were categorized as rapid and poor metabolizers. Molecular typing of CYP2C9*1 (wild type), CYP2C9*2 , and CYP2C9*3 (the most common variant) was carried out by single-base primer extension technology for 37 subjects, of which 9 were poor metabolizers, and 28 were rapid metabolizers. 14.28 % of the studied population was identified as poor metabolizer for the category of drugs metabolized by CYP2C9. Significant difference was observed between the mean ratio (drug/metabolite) of poor (11.38 ± 5.88) and rapid (1.18 ± 1.11) drug metabolizers. The study suggests that phenotyping of CYP2C9 is desirable before enrollment of subjects for clinical trials or for deciding drug dose regimen as 14.28 % of study population was found to be poor metabolizer for the category of drugs metabolized by CYP2C9. This study establishes phenotype–genotype correlation, and proposes to use genotyping or phenotyping to evaluate the status of drug metabolizing capacity of CYP2C9 as a primary screening procedure before enrolling subjects in clinical trials or in clinical practice.
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