Clopidogrel resistance

Abstract

Clopidogrel is an inactive prodrug requiring several biotransformation steps, mediated mainly by cytochrome P-450 isoforms (CYP), in order to generate an active metabolite (AM) that binds irreversibly to the platelet ADP receptor P2Y12. It was reported that polymorphism of CYP2C19 affects the pharmacokinetics of the AM and the pharmacodynamic response to clopidogrel. The prevalence of CYP2C19 poor metabolizers (PMs) is much greater (18% to 23%) in Asian people than that (3% to 5%) in Caucasian American or European populations. Therefore, in this study, in Japanese healthy subjects, we investigated whether the polymorphism of CYP2C19 would affect the formation of the AM and antiplatelet effects to the AM. 300 mg clopidogrel was orally given to 47 subjects in single dose study. The mean AUC and Cmax of the AM differed significantly (P<0.05) between the extensive metabolizers (EMs) and the intermediate metabolizers, as well as EMs and the PMs. Moreover, the pharmacokinetic parameters of the AM correlated well with the inhibition of ADP-induced platelet aggregation. These findings suggest that the CYP2C19 pharmacogenomic status is a determinant for the formation of the AM in Japanese healthy subjects.