Cytochrome P450 2C19 Polymorphism is Associated with Reduced Clopidogrel Response in Cerebrovascular Disease

ABSTRACT

PURPOSE: Clopidogrel is a prodrug that requires transformation into an active metabolite by cytochrome P450 (CYP) in the liver in order to irreversibly inhibit the P2Y12 adenosine diphosphate platelet receptor. CYP2C19 polymorphism has been reported to correlate with reduced antiplatelet activity of clopidogrel in coronary artery disease. We assessed the association between CYP2C19 polymorphism and clopidogrel resistance in patients with cerebrovascular disease. MATERIALS AND METHODS: We retrospectively gathered data from patients who experienced cerebrovascular disease, received clopidogrel, and were tested for clopidogrel resistance and CYP2C19 polymorphism. Clopidogrel resistance was tested by the VerifyNow P2Y12 system, and the CYP2C19 polymorphism was tested by the Seeplex CYP2C19 ACE Genotyping system. Clopidogrel resistance was expressed in P2Y12 reaction units (PRU) and percent inhibition. High PRU and low percent inhibition suggests clopidogrel resistance. CYP2C19 polymorphisms were expressed as extensive, intermediate, and poor metabolizers. Clopidogrel resistance was assessed according to the subgroup of CYP2C19 polymorphism. RESULTS: A total of 166 patients were evaluated. The PRU values of extensive CYP2C19 metabolizers (195.0+/-84.9) were significantly lower than those of intermediate and poor metabolizers (237.9+/-88.0, 302.2+/-58.9). The percent inhibition of extensive metabolizers (44.6+/-21.8) was significantly higher than that of intermediate and poor metabolizers (30.5+/-21.5, 14.0+/-13.4). CONCLUSION: Intermediate and poor metabolizing CYP2C19 polymorphism is associated with reduced clopidogrel antiplatelet activity in patients with cerebrovascular disease. The clinical implications of this finding require further investigation.