title: Cytochrome P450 2C19 polymorphism is associated with reduced clopidogrel response in cerebrovascular disease.
abstract: OBJECTIVE
  Clopidogrel is a prodrug that requires transformation into an active metabolite by cytochrome P450 (CYP) in the liver in order to irreversibly inhibit the P2Y12 adenosine diphosphate platelet receptor. CYP2C19 polymorphism has been reported to correlate with reduced antiplatelet activity of clopidogrel in coronary artery disease. We assessed the association between CYP2C19 polymorphism and clopidogrel resistance in patients with cerebrovascular disease.
  
  
  METHODS
  We retrospectively gathered data from patients who experienced cerebrovascular disease, received clopidogrel, and were tested for clopidogrel resistance and CYP2C19 polymorphism. Clopidogrel resistance was tested by the VerifyNow P2Y12 system, and the CYP2C19 polymorphism was tested by the Seeplex CYP2C19 ACE Genotyping system. Clopidogrel resistance was expressed in P2Y12 reaction units (PRU) and percent inhibition. High PRU and low percent inhibition suggests clopidogrel resistance. CYP2C19 polymorphisms were expressed as extensive, intermediate, and poor metabolizers. Clopidogrel resistance was assessed according to the subgroup of CYP2C19 polymorphism.
  
  
  RESULTS
  A total of 166 patients were evaluated. The PRU values of extensive CYP2C19 metabolizers (195.0±84.9) were significantly lower than those of intermediate and poor metabolizers (237.9±88.0, 302.2±58.9). The percent inhibition of extensive metabolizers (44.6±21.8) was significantly higher than that of intermediate and poor metabolizers (30.5±21.5, 14.0±13.4).
  
  
  CONCLUSIONS
  Intermediate and poor metabolizing CYP2C19 polymorphism is associated with reduced clopidogrel antiplatelet activity in patients with cerebrovascular disease. The clinical implications of this finding require further investigation.
authors.affiliation: Department of Neurology, Severance Institute for Vascular and Metabolic Research, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jun-Beom
authors.initials: JB
authors.lastname: Lee
authors.forename: Kyung-A
authors.initials: KA
authors.lastname: Lee
authors.forename: Kyung-Yul
authors.initials: KY
authors.lastname: Lee
mesh_terms: D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D002561:Cerebrovascular Disorders / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D000077144:Clopidogrel; D065731:Cytochrome P-450 CYP2C19; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D013988:Ticlopidine