Abstract
We evaluated the effect of CYP2C19 genotype over time on the antiplatelet response of clopidogrel in healthy subjects. Seventy subjects enrolled for a pharmacodynamic study and 22 subjects for a pharmacokinetic and pharmacodynamic study took 300 mg clopidogrel on the first day and 75 mg once daily for six consecutive days. The subjects with CYP2C19 poor metabolizers (PM, N = 22) and intermediate metabolizers (IM, N = 37) had significantly delayed time to inhibition of platelet aggregation (IPA) compared with CYP2C19 extensive metabolizers (EM, N = 33) (12 vs. 9 vs. 2 hours as median Tmax , P < .05) after a 300 mg of clopidogrel. During maintenance doses of clopidogrel, IPA values of only CYP2C19 PM subjects were gradually decreased from 30.0 ± 21.9% on day 2 to 23.7 ± 16.6% on day 8 (P > .05 for time effect; P < .05 for time and genotype interaction effect). CYP2C19 PM had decreased Cmax and AUC of thiol metabolite compared with CYP2C19 EM (0.42- and 0.37-fold on day 1, P < .01; 0.39- and 0.34-fold on day 7, P < .01, respectively). Delayed time to reach maximal IPA as well as decreased IPA may influence the increased risk of the acute cardiac events in CYP2C19 PM and IM.
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