PT  - JOURNAL ARTICLE
AU  - Jean-Marie Pereillo
AU  - Mohamed Maftouh
AU  - Alain Andrieu
AU  - Marie-Francoise Uzabiaga
AU  - Olivier Fedeli
AU  - Pierre Savi
AU  - Marc Pascal
AU  - Jean-Marc Herbert
AU  - Jean-Pierre Maffrand
AU  - Claudine Picard
TI  - Structure and Stereochemistry of the Active Metabolite of Clopidogrel
AID  - 10.1124/dmd.30.11.1288
DP  - 2002 Nov 01
TA  - Drug Metabolism and Disposition
PG  - 1288--1295
VI  - 30
IP  - 11
4099  - http://dmd.aspetjournals.org/content/30/11/1288.short
4100  - http://dmd.aspetjournals.org/content/30/11/1288.full
SO  - Drug Metab Dispos2002 Nov 01; 30
AB  - Clopidogrel (SR25990C, PLAVIX) is a potent antiplatelet drug, which has been recently launched and is indicated for the prevention of vascular thrombotic events in patients at risk. Clopidogrel is inactive in vitro, and a hepatic biotransformation is necessary to express the full antiaggregating activity of the drug. Moreover, 2-oxo-clopidogrel has been previously suggested to be the essential key intermediate metabolite from which the active metabolite is formed. In the present paper, we give the evidence of the occurrence of an in vitro active metabolite after incubation of 2-oxo-clopidogrel with human liver microsomes. This metabolite was purified by liquid chromatography, and its structure was studied by a combination of mass spectometry (MS) and NMR experiments. MS results suggested that the active metabolite belongs to a family of eight stereoisomers with the following primary chemical structure: 2-{1-[1-(2-chlorophenyl)-2-methoxy-2-oxoethyl]-4-sulfanyl-3-piperidinylidene}acetic acid. Chiral supercritical fluid chromatography resolved these isomers. However, only one of the eight metabolites retained the biological activity, thus underlining the critical importance of associated absolute configuration. Because of its highly labile character, probably due to a very reactive thiol function, structural elucidation of the active metabolite was performed on the stabilized acrylonitrile derivative. Conjunction of all our results suggested that the active metabolite is of S configuration at C 7 and Z configuration at C 3–C 16 double bound. The American Society for Pharmacology and Experimental Therapeutics