title: CYP2C19 but not PON1 genetic variants influence clopidogrel pharmacokinetics, pharmacodynamics, and clinical efficacy in post-myocardial infarction patients.
abstract: BACKGROUND
  Reduced concentrations of clopidogrel active metabolite have been associated with diminished platelet inhibition and higher rates of adverse cardiovascular events. Paraoxonase-1 (PON1) has recently been proposed as a key enzyme for clopidogrel metabolic activation. We tested the effects of PON1 polymorphisms on clopidogrel pharmacokinetics and pharmacodynamics and the occurrence of cardiovascular outcomes in young post-myocardial infarction (MI) patients treated with clopidogrel.
  
  
  RESULTS
  We genotyped PON1 (Q192R and L55M) and CYP2C19 variants in 106 patients enrolled in the PK/PD CLOVIS-2 trial. Patients were randomly exposed to a 300-mg or 900-mg clopidogrel loading dose in a crossover study design. Clopidogrel active metabolite isomer H4 (clopi-H4) and platelet function testing were measured serially after loading dose. There was no significant association between PON1 Q192R or L55M and clopi-H4 formation or antiplatelet response to clopidogrel after either loading dose. Using multivariable linear regression analyses, the CYP2C19*2 allele was the only predictor of clopi-H4 generation and platelet response irrespective of the platelet function assay. CYP2C19 loss-of-function but not PON1 variants were significantly associated with increased risk of major cardiovascular events (death, MI, and urgent coronary revascularization) occurring during long-term clopidogrel exposure in 371 young post-MI patients (age <45 years) enrolled in the AFIJI cohort (CYP2C19 loss-of-function allele carrier versus noncarrier: hazard ratio, 2.26; 95% confidence interval, 1.15-4.41, P=0.02; PON1 QQ192 versus QR/RR192: hazard ratio, 1.03; 95% confidence interval, 0.50-2.11, P=0.93; PON1 LL55 versus LM/MM55: hazard ratio, 1.52; 95% confidence interval, 0.75-3.08, P=0.24).
  
  
  CONCLUSIONS
  Our study does not confirm that PON1 Q192R or L55M can influence clopidogrel pharmacokinetics or pharmacodynamics in post-MI patients.
authors.affiliation: Université Pierre et Marie Curie-Paris 6, INSERM UMR S 956, Pharmacology Department, Pitié-Salpêtrière University Hospital, Paris, France.
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Hulot
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Collet
authors.forename: Guillaume
authors.initials: G
authors.lastname: Cayla
authors.forename: Johanne
authors.initials: J
authors.lastname: Silvain
authors.forename: Frédérick
authors.initials: F
authors.lastname: Allanic
authors.forename: Anne
authors.initials: A
authors.lastname: Bellemain-Appaix
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Scott
authors.forename: Gilles
authors.initials: G
authors.lastname: Montalescot
mesh_terms: D000328:Adult; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D043303:Aryldialkylphosphatase / Q000235:genetics / Q000378:metabolism; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D000077144:Clopidogrel; D015331:Cohort Studies; D018592:Cross-Over Studies; D065731:Cytochrome P-450 CYP2C19; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D010979:Platelet Function Tests; D011110:Polymorphism, Genetic; D012307:Risk Factors; D016019:Survival Analysis; D013988:Ticlopidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood; D016896:Treatment Outcome
chemical_list: D054316:Biomarkers, Pharmacological; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; D013988:Ticlopidine