title: Influence of paraoxonase-1 Q192R and cytochrome P450 2C19 polymorphisms on clopidogrel response.
abstract: BACKGROUND
  The metabolic activation of clopidogrel is a two-step process. It has been suggested that paraoxonase-1 (PON1) is a rate-limiting enzyme in the conversion of 2-oxo- clopidogrel to an active thiol metabolite. Conflicting results have been reported in regard to (1) the association of a common polymorphism of PON1 (Q192R) with reduced rates of coronary stent thrombosis in patients taking clopidogrel and (2) its effects on platelet inhibition in patient populations of European descent.
  
  
  METHODS
  Blood samples from 151 subjects of mixed racial background with established coronary artery disease and who received clopidogrel were analyzed. Platelet aggregation was determined with light transmittance aggregometry and VerifyNow(®) P2Y12 assay. Genotyping for cytochrome P450 2C19 (CYP2C19)*2 and *3 and PON1 (Q192R) polymorphisms was performed.
  
  
  RESULTS
  Carriers of CYP2C19*2 alleles exhibited lower levels of platelet inhibition and higher on-treatment platelet aggregation than noncarriers. There was no significant difference in platelet aggregation among PON1 Q192R genotypes. Homozygous carriers of the wild-type variant of PON1 (QQ192) had similar on-treatment platelet reactivity to carriers of increased-function variant alleles during maintenance clopidogrel dosing, as well as after administration of a clopidogrel 600 mg loading dose.
  
  
  CONCLUSIONS
  CYP2C19*2 allele is associated with impaired platelet inhibition by clopidogrel and high on-treatment platelet aggregation. PON1 (Q192R) polymorphism does not appear to be a significant determinant of clopidogrel response.
authors.affiliation: Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Rolf P
authors.initials: RP
authors.lastname: Kreutz
authors.forename: Perry
authors.initials: P
authors.lastname: Nystrom
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Kreutz
authors.forename: Jia
authors.initials: J
authors.lastname: Miao
authors.forename: Zeruesenay
authors.initials: Z
authors.lastname: Desta
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Breall
authors.forename: Lang
authors.initials: L
authors.lastname: Li
authors.forename: Chienwei
authors.initials: C
authors.lastname: Chiang
authors.forename: Richard
authors.initials: R
authors.lastname: Kovacs
authors.forename: David A
authors.initials: DA
authors.lastname: Flockhart
authors.forename: Yan
authors.initials: Y
authors.lastname: Jin