Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects.

The capacity of clopidogrel to inhibit ADP-induced platelet aggregation shows wide intersubject 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 28 healthy white male volunteers treated for 7 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 8 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 muM ADP decreased gradually during treatment with clopidogrel 75 mg once daily in *1/*1 subjects, reaching 48.9% +/- 14.9% on day 7 (P < .001 vs baseline), whereas it did not change in *1/*2 subjects (71.8% +/- 14.6% on day 7, P = .22 vs baseline, and P < .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.

[1]  Deepak L. Bhatt,et al.  Aspirin and clopidogrel resistance: an emerging clinical entity. , 2006, European heart journal.

[2]  D. Goldstein,et al.  Drug‐metabolizing enzymes: Evidence for clinical utility of pharmacogenomic tests , 2005, Clinical pharmacology and therapeutics.

[3]  R. Collins,et al.  Addition of clopidogrel to aspirin in 45 852 patients with acute myocardial infarction: randomised placebo-controlled trial , 2005, The Lancet.

[4]  B. Lewis,et al.  Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. , 2005, JAMA.

[5]  E. Antman,et al.  Randomized Comparison of Prasugrel (CS-747, LY640315), a Novel Thienopyridine P2Y12 Antagonist, With Clopidogrel in Percutaneous Coronary Intervention: Results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)–TIMI 26 Trial , 2005, Circulation.

[6]  O. Pelkonen,et al.  Effect of Clopidogrel and Ticlopidine on Cytochrome P450 2B6 Activity as Measured by Bupropion Hydroxylation , 2005, Clinical pharmacology and therapeutics.

[7]  G. Wilkinson,et al.  Drug metabolism and variability among patients in drug response. , 2005, The New England journal of medicine.

[8]  E. Bates,et al.  Loading, Pretreatment, and Interindividual Variability Issues With Clopidogrel Dosing , 2005, Circulation.

[9]  J. Diodati,et al.  Resistance to clopidogrel: a review of the evidence. , 2005, Journal of the American College of Cardiology.

[10]  A. Kastrati,et al.  P2Y12 gene H2 haplotype is not associated with increased adenosine diphosphate-induced platelet aggregation after initiation of clopidogrel therapy with a high loading dose , 2005, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[11]  C. Gachet,et al.  Flow cytometric analysis of intraplatelet VASP phosphorylation for the detection of clopidogrel resistance in patients with ischemic cardiovascular diseases , 2005, Journal of thrombosis and haemostasis : JTH.

[12]  E. Trabetti,et al.  Lack of association between the P2Y12 receptor gene polymorphism and platelet response to clopidogrel in patients with coronary artery disease. , 2005, Thrombosis research.

[13]  M. Cattaneo Aspirin and Clopidogrel: Efficacy, Safety, and the Issue of Drug Resistance , 2004, Arteriosclerosis, thrombosis, and vascular biology.

[14]  H. Hod,et al.  Clopidogrel Resistance Is Associated With Increased Risk of Recurrent Atherothrombotic Events in Patients With Acute Myocardial Infarction , 2004, Circulation.

[15]  P. Watkins,et al.  Contribution of Hepatic Cytochrome P450 3A4 Metabolic Activity to the Phenomenon of Clopidogrel Resistance , 2004, Circulation.

[16]  M. Eichelbaum,et al.  Potent Mechanism-Based Inhibition of Human CYP2B6 by Clopidogrel and Ticlopidine , 2004, Journal of Pharmacology and Experimental Therapeutics.

[17]  R. de Caterina,et al.  Expert consensus document on the use of antiplatelet agents. The task force on the use of antiplatelet agents in patients with atherosclerotic cardiovascular disease of the European society of cardiology. , 2004, European heart journal.

[18]  Kevin P. Bliden,et al.  Clopidogrel for Coronary Stenting Response Variability, Drug Resistance, and the Effect of Pretreatment Platelet Reactivity , 2003, Circulation.

[19]  M. Maftouh,et al.  Structure and stereochemistry of the active metabolite of clopidogrel. , 2002, Drug metabolism and disposition: the biological fate of chemicals.

[20]  K. Ohashi,et al.  Effect of high‐dose lansoprazole on intragastic pH in subjects who are homozygous extensive metabolizers of cytochrome P4502C19 , 2001, Clinical pharmacology and therapeutics.

[21]  S. Yusuf,et al.  Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. , 2001, The New England journal of medicine.

[22]  David Julius,et al.  Identification of the platelet ADP receptor targeted by antithrombotic drugs , 2001, Nature.

[23]  U. Walter,et al.  Flow Cytometry Analysis of Intracellular VASP Phosphorylation for the Assessment of Activating and Inhibitory Signal Transduction Pathways in Human Platelets , 1999, Thrombosis and Haemostasis.

[24]  U. Walter,et al.  Phosphorylation of focal adhesion vasodilator-stimulated phosphoprotein at Ser157 in intact human platelets correlates with fibrinogen receptor inhibition. , 1994, European journal of biochemistry.

[25]  J. Herbert,et al.  The Antiaggregating Activity of Clopidogrel Is due to a Metabolic Activation by the Hepatic Cytochrome P450-1A , 1994, Thrombosis and Haemostasis.

[26]  G R Wilkinson,et al.  The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. , 1994, The Journal of biological chemistry.

[27]  J. Herbert,et al.  Importance of hepatic metabolism in the antiaggregating activity of the thienopyridine clopidogrel. , 1992, Biochemical pharmacology.