Contribution of Hepatic Cytochrome P450 3A4 Metabolic Activity to the Phenomenon of Clopidogrel Resistance

Abstract

Background-Interindividual variability of platelet inhibition after aspirin or clopidogrel administration has been described. Additionally, aspirin resistance and clopidogrel resistance occur in some individuals. Because the prodrug clopidogrel is activated by hepatic cytochrome P450 (CYP) 3A4, we hypothesized that interindividual variability in clopidogrel efficacy might be related to interindividual differences in CYP3A4 metabolic activity. Methods and Results-Platelet aggregation was measured before and after clopidogrel treatment in 32 patients undergoing coronary artery stent implantation and in 35 healthy volunteers. The erythromycin breath test was used to measure CYP3A4 activity in vivo in 25 of the healthy volunteers. Individual platelet aggregation was studied in 10 healthy volunteers after the coadministration of clopidogrel and rifampin (a CYP3A4 inducer). Clopidogrel nonresponders, low responders, and responders were defined by a relative inhibition of adenosine diphosphate (20 mol/L)-induced platelet aggregation of Ͻ10%, 10% to 29%, and Ն30%, respectively. Among patients, 22% were clopidogrel nonresponders, 32% were low responders, and 47% were responders. Among volunteers, 16% were nonresponders, 12% were low responders, and 72% were responders. Percent platelet aggregation after clopidogrel inversely correlated with CYP3A4 activity (rϭϪ0.6, Pϭ0.003). Improved platelet inhibition in volunteers resistant to clopidogrel was observed with the coadministration of clopidogrel and rifampin. Conclusions-Clopidogrel administration results in interindividual variability in platelet inhibition, which correlates with CYP3A4 metabolic activity. Measurement of antiplatelet drug efficacy with a point-of-care device and alternative antithrombotic strategies for aspirin or clopidogrel nonresponders and low responders could reduce the incidence of thrombotic events that continue to occur despite oral antiplatelet therapy. Key Words: drugs Ⅲ platelets Ⅲ pharmacology C lopidogrel, a thienopyridine derivative similar to ticlopidine, is an inhibitor of platelet aggregation induced by adenosine diphosphate (ADP). 1 Clopidogrel was approved by the United States Food and Drug Administration (FDA) in 1997 for the reduction of myocardial infarction, stroke, and vascular death in patients with recent stroke, recent myocardial infarction, or established peripheral arterial disease after the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial 2 showed superior reduction of these events with clopidogrel compared with aspirin (annual risk, 5.3% versus 5.8%; Pϭ0.04). Dual antiplatelet therapy (aspirin plus clopidogrel) for acute coronary syndromes was approved by the FDA in 2002 on the basis of the Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) trial 3 results, which showed a significant reduction in the 9-month composite end point of cardiovascular death, nonfatal myocardial infarction, or stroke versus aspirin monotherapy (9.3% versus 11.4%, PϽ0.001). Additionally, the c...

Aspirin and Clopidogrel

“…In published studies, Ϸ50% of the patients were either clopidogrel nonresponders or low responders. 85 Interindividual variability in platelet inhibition by clopidogrel correlated well with the metabolic activity of the hepatic cytochrome P450, which activates the prodrug to its active metabolite. 86 Whether polymorphisms of the clopidogrel target, P2Y 12 , play additional roles in modulating the individual response is presently unknown.…”

Investigating the Mechanisms of Hyporesponse to Antiplatelet Approaches

“…26,27 Lau and colleagues sought to determine whether variations in CYP3A4 activity contribute to clopidogrel variability in platelet inhibition by measuring platelet aggregation in 32 patients undergoing PCI with stenting and 35 healthy volunteers. 28 According to the degree of ADPinduced platelet aggregation, 22% and 16% were classified as clopidogrel nonresponders, 32% and 12% as low responders, and 47% and 72% as responders among patients and healthy volunteers, respectively; an inverse correlation was found between platelet activation and CYP3A4 activity (p = 0.003). Coadministration with the CYP3A4 inducer rifampin was found to significantly enhance clopidogrel's inhibition of platelet aggregation versus clopidogrel alone (p = 0.001); in fact, 3 clopidogrel nonresponders subsequently became clopidogrel responders after rifampin administration.…”

Controversies in Antiplatelet Therapy for Patients With Cardiovascular Disease

“…22 As with aspirin, variable platelet aggregation inhibition after clopidogrel occurs among individuals; nonresponders to clopidogrel have been identified. 23,24 One major mechanism may be the failure of clopidogrel, a prodrug, to be metabolized to its active metabolite by hepatic cytochrome P450 (CYP) 3A4. 24 Multiple other possible mechanisms include underdosing, impaired gastric absorption, ADP receptor P 2 Y 12 polymorphisms, and intracellular signaling variability.…”