title: Impact of CYP2C19 polymorphisms on the antiplatelet effect of clopidogrel in an actual clinical setting in Japan.
abstract: 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.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Jinnai
authors.forename: Hisanori
authors.initials: H
authors.lastname: Horiuchi
authors.forename: Takeru
authors.initials: T
authors.lastname: Makiyama
authors.forename: Junichi
authors.initials: J
authors.lastname: Tazaki
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Tada
authors.forename: Masaharu
authors.initials: M
authors.lastname: Akao
authors.forename: Koh
authors.initials: K
authors.lastname: Ono
authors.forename: Kozo
authors.initials: K
authors.lastname: Hoshino
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Naruse
authors.forename: Kanako
authors.initials: K
authors.lastname: Takahashi
authors.forename: Haruyo
authors.initials: H
authors.lastname: Watanabe
authors.forename: Toru
authors.initials: T
authors.lastname: Kita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kimura
mesh_terms: 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
chemical_list: 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