The Effect of CYP2C19 Genotype on the Time Course of Platelet Aggregation Inhibition After Clopidogrel Administration

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 T-max, 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 C-max 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.