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Accueil > Equipes de recherche > Chimie Bio-inorganique des Dérivés Soufrés et Pharmacochimie > Thémes de recherche

Mechanism of the metabolic activation of anti-thrombotic drugs of the thienopyridine series.

publié le , mis à jour le

P. Dansette, D. Mansuy


Collaborators :
A. Hessani (UMR 8601)

The tetrahydrothienopyridine anti-thrombotic drugs ticlopidine, clopidogrel and prasugrel are prodrugs that must be metabolized into the pharmacologically active thiols 3 that act as irreversible inhibitors of platelet receptor P2Y12. The precise mechanisms remained poorly known.
Recent results
We studied the metabolism of clopidogrel, one of the most anti-thrombotic drug prescribed in the world, by human liver microsomes using a HPLC-MS methods allowing a clean separation of all the various possible isomers of thiol 3b.
i) CYPs, including CYP 2C19, are the only enzymes responsible for the formation of pharmacologically active cis-thiol 3b via a sulfenic acid intermediate 5b fully characterized after trapping by dimedone. Compound 5b is then reduced to 3b by glutathione.
ii) Paraoxonase-1 catalyzes the formation of minor isomer, 3b', not previously described.

Recent clinical data are in complete agreement with our results: thiol 3b is the major metabolite found in human sera of clopidogrel-treated patients whereas its isomer 3b' is only present in small amounts. We obtained similar results in the case of the recently launched anti-thrombotic drug, prasugrel 1c.
Our data revealed the importance of sulfenic acids, a new class of reactive metabolites.
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