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Blood, 1 October 2006, Vol. 108, No. 7, pp. 2244-2247. Prepublished online as a Blood First Edition Paper on June 13, 2006; DOI 10.1182/blood-2006-04-013052. This Article Full Text (PDF) All Versions of this Article: blood-2006-04-013052v1 108/7/2244    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Hulot, J.-S. Articles by Gaussem, P. Search for Related Content PubMed PubMed Citation Articles by Hulot, J.-S. Articles by Gaussem, P. Social Bookmarking                   What's this?  Previous Article  |  Next Article  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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. W. Hamm Current practice and limitations of dual antiplatelet therapy in acute coronary syndrome Eur. Heart J. Suppl., December 1, 2009; 11(suppl_G): G4 - G8. [Abstract] [Full Text] [PDF] K. Hagihara, M. Kazui, A. 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