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Identification and Biological Activity of the Active Metabolite of Clopidogrel

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
Issue: 2000: 84/5 (Nov) pp.740-934
Pages: 891-896

Identification and Biological Activity of the Active Metabolite of Clopidogrel

P. Savi, J. M. Pereillo, M. F. Uzabiaga, J. Combalbert, C. Picard, J. P. Maffrand, M. Pascal, J. M. Herbert
From Sanofi-Synthélabo, Toulouse, Montpellier and Labège, France


Like ticlopidine, the ADP receptor antagonist clopidogrel is inactive in vitro and must be administered i.v. or orally to exhibit antiaggrega-tory and antithrombotic activities. We have previously shown that he-patic metabolism is necessary for activity. This study demonstrates that an active metabolite can be generated from human liver microsomes incubated with clopidogrel. Using several analytical methodologies (LC/MS, NMR, chiral supercritical fluid chromatography), we have identified its structure. In vitro, this highly unstable compound, different from that formed from ticlopidine, exhibited all the biological activities of clopidogrel observed ex vivo: Irreversible inhibition of the binding of 33 P-2MeS-ADP to washed human platelets (IC 50 = 0.53 μM), selective inhibition of ADP-induced platelet aggregation (IC 50 = 1.8 μM) and ADP-induced adenylyl cyclase down-regulation. The irreversible modification of the ADP-receptor site which is responsible for the biological activity could be explained by the formation of a disulfide bridge between the reactive thiol group of the active metabolite and a cysteine residue of the platelet ADP receptor.