CYP2C19 but not PON1 genetic variants influence clopidogrel pharmacokinetics, pharmacodynamics, and clinical efficacy in post-myocardial infarction patients

Jean Sébastien Hulot, Jean Philippe Collet, Guillaume Cayla, Johanne Silvain, Frédérick Allanic, Anne Bellemain-Appaix, Stuart A. Scott, Gilles Montalescot

Research output: Contribution to journalArticlepeer-review

101 Scopus citations

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. Methods and 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. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00822666.

Original languageEnglish
Pages (from-to)422-428
Number of pages7
JournalCirculation: Cardiovascular Interventions
Volume4
Issue number5
DOIs
StatePublished - Oct 2011

Keywords

  • Clopidogrel
  • Coronary artery disease
  • Coronary stenting
  • Cytochrome P450
  • Genetic polymorphisms
  • Myocardial infarction
  • Paraoxonase-1
  • Pharmacokinetics
  • Platelets

Fingerprint

Dive into the research topics of 'CYP2C19 but not PON1 genetic variants influence clopidogrel pharmacokinetics, pharmacodynamics, and clinical efficacy in post-myocardial infarction patients'. Together they form a unique fingerprint.

Cite this