Effects of CYP2C19 Genetic Polymorphisms on the Pharmacokinetic and Pharmacodynamic Properties of Clopidogrel and Its Active Metabolite in Healthy Chinese Subjects

Abstract Purpose Some studies in the white population have shown that carriers of at least 1 loss-of-function allele in the gene that encodes the cytochrome P-450 2C19 isozyme ( CYP2C19 ) have lower levels of the clopidogrel active metabolite (CAM) and a reduced antiplatelet effect of clopidogrel. However, data are limited regarding the association between CYP2C19 genetic variants and exposure to CAM and on the pharmacodynamic properties of CAM in the Chinese population. Data from the white population cannot be extrapolated to the Chinese population because of the marked interethnic differences in CYP2C19 variants. This study was aimed to investigate the influence of CYP2C19 genetic polymorphisms on the pharmacokinetic properties of CAM and the antiplatelet effect of clopidogrel in healthy Chinese volunteers, and to provide evidence for the role of a CYP2C19 genotyping test in predicting the antiplatelet effect of clopidogrel in the Chinese population. Methods Twenty healthy subjects received a single 300-mg dose of clopidogrel and were assigned to 1 of 3 groups according to CYP2C19 genotype: CYP2C19 *1/*1 (normal metabolizers [NM]; n = 8), CYP2C19 *1/*2 or *3 (intermediate metabolizers [IM]; n = 10) and CYP2C19 *2/*2 or *3 and *3/*3 (poor metabolizers [PM]; n = 2). Blood samples were collected at baseline and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after administration. The plasma concentrations of clopidogrel and CAM were analyzed by LC-MS/MS, and adenosine diphosphate–induced platelet aggregation was measured by light-transmittance aggregometry. Findings There were no significant differences in C max and AUC 0–t of clopidogrel prodrug in the NM group compared with the IM and PM groups. The mean CAM C max value was significantly higher in the NM group than in IM and PM groups (45.39 [12.57] vs 29.15 [7.92] ng/mL [ P  = 0.003] and 19.55 [2.19] ng/mL [ P  = 0.004], respectively). The mean CAM AUC 0–t value was significantly higher in the NM group than in the IM and PM groups (61.05 [21.63] vs 37.67 [11.01] ng · h/mL [ P  = 0.007] and 27.08 [2.72] ng · h/mL [ P  = 0.016]). The NM group exhibited a significantly higher percentage of inhibition of platelet aggregation than did the IM or PM group ( P  = 0.001). The correlations between the pharmacokinetic properties (C max , AUC 0–t) of CAM and the pharmacodynamic data (maximal and inhibition of platelet aggregation) were significant (both, Pearson r > 0.5 and P 0.01). Implication In these healthy Chinese subjects, carriers of CYP2C19 loss-of-function allele(s) had significantly reduced exposure of CAM and decreased levels of inhibition of platelet aggregation with clopidogrel; these genotypes therefore might be a determinant for the formation of CAM and its antiplatelet effects. Study identifier: ChiCTR-OCH-14004382.