title: Prediction of clopidogrel low responders by a rapid CYP2C19 activity test.
abstract: OBJECTIVE
  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 (13)C-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 ((13)CO(2)/(12)CO(2)) in expiration gas between before and after (13)C-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 (13)C-pantoprazole breath test can detect CYP2C19 PMs and predict low responders to clopidogrel rapidly.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Tazaki
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Jinnai
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Tada
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kato
authors.forename: Takeru
authors.initials: T
authors.lastname: Makiyama
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Ikeda
authors.forename: Keiichiro
authors.initials: K
authors.lastname: Yamane
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: Takeshi
authors.initials: T
authors.lastname: Kimura
authors.forename: Hisanori
authors.initials: H
authors.lastname: Horiuchi
mesh_terms: D053799:2-Pyridinylmethylsulfinylbenzimidazoles / Q000493:pharmacokinetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism*; D001944:Breath Tests; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D005838:Genotype; D006801:Humans; D008297:Male; D000077402:Pantoprazole; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011110:Polymorphism, Genetic / Q000235:genetics; D011379:Prognosis; D054328:Proton Pump Inhibitors / Q000493:pharmacokinetics; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D002250:Carbon Radioisotopes; D010975:Platelet Aggregation Inhibitors; D054328:Proton Pump Inhibitors; D000077144:Clopidogrel; D000077402:Pantoprazole; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine