on January 5, 2004
Circulation. 2004
Published online before print January 5, 2004, doi: 10.1161/01.CIR.0000112378.09325.F9
Published online before print January 5, 2004, doi: 10.1161/01.CIR.0000112378.09325.F9
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© American Heart Association, Inc.
Clinical Investigation and Reports |
Contribution of Hepatic Cytochrome P450 3A4 Metabolic Activity to the Phenomenon of Clopidogrel Resistance
From the Department of Anesthesiology (W.C.L., C.J.N., A.S.H., A.R.T.), University of Michigan, Ann Arbor, Mich; Sinai Center for Thrombosis Research (P.A.G.), Sinai Hospital of Baltimore, Baltimore, Md; General Clinical Research Center (P.B.W.), University of North Carolina, Chapel Hill, NC; Division of Thrombosis (D.G.M.C., K.E.G.), Department of Chemistry, Indiana University, South Bend, Indiana; and Division of Cardiovascular Diseases (E.R.B.), Department of Internal Medicine, University of Michigan, Ann Arbor, Mich.
Correspondence to Wei C. Lau, MD, Department of Anesthesiology, University of Michigan Health System, 1G323 University Hospital, Box 0048, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0048. E-mail weiclau{at}umich.edu
Received August 29, 2003; de novo received October 9, 2003; revision received November 10, 2003; accepted November 25, 2003.
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 µmol/L)–induced platelet aggregation of <10%, 10% to 29%, and 
30%, 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 (r=-0.6, P=0.003). 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 • platelets • pharmacology
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