CYP 2 C 19 But Not PON 1 Genetic Variants Influence Clopidogrel Pharmacokinetics , Pharmacodynamics , and Clinical Efficacy in Post – Myocardial Infarction Patients
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. (Circ Cardiovasc Interv. 2011;4:422-428.)