Impact of CYP2C19 polymorphisms on the antiplatelet effect of clopidogrel in an actual clinical setting in Japan.
BACKGROUND
The P2Y(12) 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 P2Y(12) on the antiplatelet effect of clopidogrel in clinical patients was examined in the present study.


RESULTS
Single nucleotide polymorphisms of CYP2C19*2, *3, CYP3A4 (IVS10 +12G>A) and P2Y(12) (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 micromol/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.
Jinnai
Toshikazu
T
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Horiuchi
Hisanori
H
Makiyama
Takeru
T
Tazaki
Junichi
J
Tada
Tomohisa
T
Akao
Masaharu
M
Ono
Koh
K
Hoshino
Kozo
K
Naruse
Yumiko
Y
Takahashi
Kanako
K
Watanabe
Haruyo
H
Kita
Toru
T
Kimura
Takeshi
T
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D006801:Humans; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide / Q000502:physiology*; D018048:Receptors, Purinergic P2 / Q000235:genetics; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology
D010975:Platelet Aggregation Inhibitors; D018048:Receptors, Purinergic P2; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D013988:Ticlopidine