Very slow chiral inversion of clopidogrel in rats: a pharmacokinetic and mechanistic investigation.

Détails

ID Serval
serval:BIB_14802
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Very slow chiral inversion of clopidogrel in rats: a pharmacokinetic and mechanistic investigation.
Périodique
Drug Metabolism and Disposition
Auteur(s)
Reist M., Roy-de Vos M., Montseny J.P., Mayer J.M., Carrupt P.A., Berger Y., Testa B.
ISSN
0090-9556
Statut éditorial
Publié
Date de publication
2000
Volume
28
Numéro
12
Pages
1405-1410
Langue
anglais
Notes
Publication types: In Vitro ; Journal Article Publication Status: ppublish
Résumé
Clopidogrel hydrogen sulfate, a thienopyridine derivative, is an ADP receptor antagonist that inhibits platelet aggregation. Clopidogrel is an enantiopure carboxylic ester of S-configuration. The R-enantiomer is devoid of antithrombotic activity and can provoke convulsions at high doses in animals. During preclinical safety evaluation, the possible chiral inversion of clopidogrel has, therefore, been investigated in vivo after repeated oral administration of different dose levels of clopidogrel to male and female rats. Due to rapid metabolism in the liver and low plasma levels of unchanged drug, possible chiral inversion was assessed by monitoring the plasma concentrations of the carboxylic acid metabolites, i.e., the (S)- and (R)-acid, by means of a stereoselective assay. The production of 4 to 8% of (R)-acid was observed. This could be the result of chiral inversion of either clopidogrel or its main metabolite, the (S)-acid. Thus, the possibility of nonenzymatic and enzymatic inversion of clopidogrel and its carboxylic acid metabolite was studied in vitro by chiral HPLC and (1)H NMR. Nonenzymatic chiral inversion of clopidogrel at 37 degrees C in 0.1 M phosphate buffers could be observed but was found to be slow, with estimated half-lives of 7 to 12 days, depending on the pH. The (S)-acid was configurationally fully stable up to 45 days in phosphate buffers. Neither clopidogrel nor its carboxylic acid metabolites were subject to enzymatic chiral inversion in isolated rat hepatocyte suspensions. We conclude that the nonenzymatic inversion of clopidogrel accounts for the 4 to 8% of chiral inversion seen in vivo in the rat.
Mots-clé
Algorithms, Animals, Chromatography, High Pressure Liquid, Half-Life, Hepatocytes/metabolism, Hydrolysis, Platelet Aggregation Inhibitors/metabolism, Platelet Aggregation Inhibitors/pharmacokinetics, Rats, Rats, Sprague-Dawley, Spectrophotometry, Ultraviolet, Stereoisomerism, Ticlopidine/analogs & derivatives, Ticlopidine/metabolism
Pubmed
Web of science
Création de la notice
19/11/2007 10:35
Dernière modification de la notice
20/08/2019 13:43
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