Submitted April 7, 2006
Accepted May 29, 2006
Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects
Jean-Sebastien Hulot, Alessandra Bura, Eric Villard, Michel Azizi, Veronique Remones, Catherine Goyenvalle, Martine Aiach, Philippe Lechat, and Pascale Gaussem*
Service de pharmacologie, Hopital Pitie Salpetriere, Inserm UMR S 621, Paris, France
Service d'Hematologie Biologique, Universite Paris-Descartes, Inserm Unite U765, Paris, France
AP-HP, Hopital Pitie-Salpetriere, Centre d'Investigations Biomedicales, Paris, France
AP-HP, Hopital Europeen Georges Pompidou, INSERM, CIC 9201, Universite Paris-Descartes, Paris,France
* Corresponding author; email: pascale.gaussem{at}egp.aphp.fr.
The capacity of clopidogrel to inhibit ADP-induced platelet aggregation shows wide inter-subject variability. To determine whether frequent functional variants of genes coding for candidate cytochrome P450 (CYP) isoenzymes involved in clopidogrel metabolic activation (CYP2C19*2, CYP2B6*5, CYP1A2*1F and CYP3A5*3 variants) influence the platelet responsiveness to clopidogrel, we conducted a prospective pharmacogenetic study in twenty-eight healthy Caucasian male volunteers treated for seven days with clopidogrel 75 mg/d.
We observed that pharmacodynamic response to clopidogrel was significantly associated with the CYP2C19 genotype. Twenty of the subjects were wild-type CYP2C19 (*1/*1) homozygotes, while the other eight subjects were heterozygous for the loss-of-function polymorphism CYP2C19*2 (*1/*2). Baseline platelet activity was not influenced by the CYP2C19 genotype. In contrast, platelet aggregation in the presence of 10 µ mol/L ADP decreased gradually during treatment with clopidogrel 75 mg once daily in *1/*1 subjects, reaching 48.9± 14.9% on day 7 (p<0.0001 vs baseline), whereas it did not change in *1/*2 subjects (71.8± 14.6% on day 7, p=0.22 vs baseline, and p<0.003 vs *1/*1 subjects). Similar results were found with VASP phosphorylation.
The CYP2C19*2 loss-of-function allele is associated with a marked decrease in platelet responsiveness to clopidogrel in young healthy male volunteers and may therefore be an important genetic contributor to clopidogrel resistance in the clinical setting.
