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.

METHODS AND 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: Toshikazu Jinnai, Hisanori Horiuchi, Takeru Makiyama, Junichi Tazaki, Tomohisa Tada, Masaharu Akao, Koh Ono, Kozo Hoshino, Yumiko Naruse, Kanako Takahashi, Haruyo Watanabe, Toru Kita, Takeshi Kimura
• Journal: Circulation journal : official journal of the Japanese Circulation Society (Circ J) Vol. 73 Issue 8 Pg. 1498-503 (Aug 2009) ISSN: 1347-4820 [Electronic] Japan
• PMID: 19531897 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Platelet Aggregation Inhibitors
• Receptors, Purinergic P2
• Adenosine Diphosphate
• Clopidogrel
• Aryl Hydrocarbon Hydroxylases
• CYP2C19 protein, human
• Cytochrome P-450 CYP2C19
• Cytochrome P-450 CYP3A
• CYP3A4 protein, human
• Ticlopidine

Topics

• Adenosine Diphosphate (pharmacology)
• Aged
• Aryl Hydrocarbon Hydroxylases (genetics)
• Clopidogrel
• Cytochrome P-450 CYP2C19
• Cytochrome P-450 CYP3A (genetics)
• Female
• Humans
• Japan (epidemiology)
• Male
• Middle Aged
• Pharmacogenetics
• Platelet Aggregation (drug effects)
• Platelet Aggregation Inhibitors (pharmacology)
• Polymorphism, Single Nucleotide (physiology)
• Receptors, Purinergic P2 (genetics)
• Ticlopidine (analogs & derivatives, pharmacology)