Prediction of Clopidogrel Low Responders by a Rapid CYP2C19 Activity Test

• Published in: Journal of Atherosclerosis and Thrombosis 2012, Vol.19(2), pp.186-193
• Main Authors: Tazaki, Junichi, Jinnai, Toshikazu, Tada, Tomohisa, Kato, Yoshihiro, Makiyama, Takeru, Ikeda, Tomoyuki, Yamane, Keiichiro, Naruse, Yumiko, Takahashi, Kanako, Watanabe, Haruyo, Kimura, Takeshi, Horiuchi, Hisanori
• Format: Article
• Language: English
• Subjects: 2-Pyridinylmethylsulfinylbenzimidazoles - pharmacokinetics; Antiplatelet therapy; Aryl Hydrocarbon Hydroxylases - genetics; Aryl Hydrocarbon Hydroxylases - metabolism; Breath Tests; Carbon Radioisotopes - pharmacokinetics; Clopidogrel; CYP2C19 polymorphism; Cytochrome P-450 CYP2C19; Genotype; Humans; Male; Pantoprazole; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - pharmacology; Polymorphism, Genetic - genetics; Prognosis; Proton Pump Inhibitors - pharmacokinetics; Ticlopidine - analogs & derivatives; Ticlopidine - pharmacology; Tissue Distribution
• ISSN: 1340-3478; 1880-3873
• DOI: 10.5551/jat.10009

Aim: Clopidogrel, an essential drug for the prevention of stent thrombosis, is a prodrug activated by CYP enzyme family including CYP2C19. It is known that activity-defective polymorphisms of CYP2C19 (CYP2C19*2 and*3) are associated with reduced clopidogrel efficacy and poor prognosis. Recently, the 13C-pantoprazole breath test is developed to evaluate the CYP2C19 activity. The aim of this study is to evaluated the efficiency of the CYP2C19 activity test as a predictor of antiplatelet effect of clopidogrel Methods: The CYP2C19 activity and the antiplatelet effect of clopidogrel were evaluated in 27 healthy volunteers. Change of the carbon isotope ratios (13CO2/12CO2) in expiration gas between before and after 13C-pantoprazole intake was evaluated as delta over baseline (DOB) ratio (‰). Results: DOB at 30 min was significantly lower in poor metabolizers (PMs) than extensive metabolizers (EMs) and intermediate metabolizers (IMs) (EM vs. PM, p=0.0108; IM vs. PM, p=0.016). The antiplatelet effect of clopidogrel was significantly different in three groups (inhibition of platelet aggregation: p=0.0148, P2Y12 reaction unit: p=0.0241). DOB at 30 min was correlated with the antiplatelet effect of clopidogrel. A cut-off value of DOB at 30 min below 1.0‰ predicted PMs with 96% specificity and 100% sensitivity. Conclusions: The 13C-pantoprazole breath test can detect CYP2C19 PMs and predict low responders to clopidogrel rapidly.