Effect of Cytochrome P450 2C19 Genetic Polymorphism and Coadministration with Ketoconazole on the Platelet Aggregation Response to Clopidogrel in Korean Healthy Subjects

한국인 건강 피험자에서 Cytochrome P450 2C19 유전적다형성과 Ketoconazole 병용투여가 Clopidogrel 투여 후 혈소판응집 반응에 미치는 영향

Background: Clopidogrel is a prodrug converted to active metabolite mainly by cytochrome P450 (CYP) enzyme, and provides clinical benefitwith wide interindividual variability. We investigated to evaluate the effect of CYP2C19 genetic polymorphism and coadministration with ketoconazole on the platelet aggregation response to clopidogrel. Methods: An open-label, two-treatment, two-period, one-way crossover study with a drug-free period of five days or more was conducted in healthy male volunteers. First, a single dose of 300 mg clopidogrel was administered to carriers of at least one CYP2C19 loss-of-function allele (n=10) and non-carriers (n = 12). After a drug-free period, a single dose of 300 mg clopidogrel was administered with400 mg ketoconazole daily for 3 days. Platelet aggregation was measured at baseline, 4 h, 6 h, and 24 h using Chronolog Lumi-Aggregometer. Results: Maximal platelet aggregation at baseline was not different across CYP2C19 genotype. CYP2C19 loss-of-function allele carriers had significantlyless reduction in platelet aggregation at 24 h than non-carriers whether clopidogrel was administered alone (P=0.018) or with ketoconazole (P=0.011). In addition, relative inhibition of platelet aggregation at 24 h was lower after coadministration with ketoconazole than clopidogrel alone (P<0.001). Conclusions: Platelet aggregation response to clopidogrel was affected by CYP2C19 genetic polymorphism and coadministration with ketoconazole.