Impact of CYP2C19 polymorphisms on the antiplatelet effect of clopidogrel in an actual clinical setting in Japan

Background: The P2Y₁₂ adenosine diphosphate (ADP) receptor blocker, clopidogrel, an essential drug for the prevention of stent thrombosis after percutaneous coronary intervention (PCI), is a prodrug that requires CYP2C19-and CYP3A4-mediating activation. CYP2C19*2 and *3 polymorphisms are known to lack enzymatic activity. CYP2C19 polymorphisms have been reported to exhibit weaker antiplatelet response to clopidogrel in healthy subjects. The effect of polymorphisms of CYP2C19, CYP3A4 and P2Y₁₂ on the antiplatelet effect of clopidogrel in clinical patients was examined in the present study. Methods and Results: Single nucleotide polymorphisms of CYP2C19*2, *3, CYP3A4 (IVS10+12G>A) and P2Y₁₂ (T744C) were determined in 25 PCI-scheduled patients who had been systematically analyzed for the antiplatelet effect of clopidogrel in a previous study. On the basis of CYP2C19 genotype, 11 patients (44%) were classified as extensive metabolizers (EMs), 8 (32%) as intermediate metabolizers (IMs) and 6 (24%) as poor metabolizers (PMs). The rates of inhibition of 5 μmol/L ADP-induced platelet aggregation by clopidogrel intake at 48 h were 31.6±14.3% in EMs, 18.4±10.0% in IMs (P=0.04 vs EMs) and 16.0±13.0% in PMs (P=0.02 vs EMs). Conclusions: CYP2C19 polymorphisms are frequent in Japanese, and the antiplatelet effect of clopidogrel is strongly affected by them in the real-world clinical setting.