Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel

Objectives—Metabolic activity of cytochrome P450 (CYP) 3A4 has been associated with clopidogrel response variability. Because metabolic activity of CYP3A4 is genetically regulated, we hypothesized that genetic variations of this enzyme may contribute to clopidogrel response variability. Methods and Results—The CYP3A4*1B, CYP3A4*3, IVS7_258A_G, IVS7_894C_T, and IVS10_12G_A polymorphisms of the CYP3A4 gene were assessed in 82 patients in a steady phase of clopidogrel therapy. Glycoprotein (platelet glycoprotein (GP) IIb/IIIa receptor activation and platelet aggregation were assessed. A cohort of 45 clopidogrel-naı¨ve patients was studied to determine the modulating effects of these polymorphisms after loading dose (300 mg) administration. Only the IVS7_258A_G, IVS7_894C_T, and IVS10_12G_A polymorphisms were sufficiently polymorphic. During the steady phase of clopidogrel treatment, IVS10_12A allele carriers had reduced GP IIb/IIIa activation (P_0.025) and better responsiveness (P_0.02); similarly, clopidogrel-naı¨ve patients carriers of the IVS10_12A allele had reduced GP IIb/IIIa activation during the first 24 hours after a loading dose (P_0.025), increased platelet inhibition (P_0.006), and a more optimal drug response (P_0.003). This polymorphism did not influence platelet aggregation profiles. No association was observed between the other polymorphisms and clopidogrel responsiveness. Conclusions—The IVS10_12G_A polymorphism of the CYP3A4 gene modulates platelet activation in patients treated with clopidogrel and may therefore contribute to clopidogrel response variability.