The impact of genetic polymorphisms of drug metabolizing enzymes on the pharmacodynamics of clopidogrel under steady state conditions

Abstract

Clopidogrel is an antiplatelet drug that requires biotransformation steps to its active metabolite via cytochromes P450 (CYP), particularly CYP2C19 and CYP3A5 as well as paraoxonase-1 (PON1). The impact of CYP3A5 and PON1 genetic polymorphisms on the response of this drug is unclear. This study aimed to elucidate the degree of genetic polymorphisms of key drug metabolizing enzymes on the antiplatelet effect of clopidogrel. Thirty-five healthy subjects were treated with 75 mg/day clopidogrel for 7 days and serial blood samples were collected for measurement of antiplatelet effect using whole blood impedance aggregometry and VerifyNow® P2Y12 methods. The areas under the antiplatelet effect–time curves, maximal and minimal antiplatelet effects of clopidogrel obtained from both methods were significantly different among subjects with different CYP2C19 genotypes. In contrast, these pharmacodymamic parameters measured by both methods of subjects with different PON1 or CYP3A5 genotypes were not significantly different. Among the heterozygous CYP2C19*2 subjects, all pharmacodynamic parameters measured by whole blood impedance aggregometry were significantly different between subjects with different CYP3A5*3 genotypes. Our data suggests that CYP2C19 genetic polymorphism play a major role in the clopidogrel response, however, the impact of CYP3A5 genetic polymorphism, may be pronounced in the subjects who carried the loss-functional allele of CYP2C19.