Contribution of Hepatic Cytochrome P450 3A4 Metabolic Activity to the Phenomenon of Clopidogrel Resistance
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Lau, Wei C, et al. Contribution of Hepatic Cytochrome P450 3a4 Metabolic Activity to the Phenomenon of Clopidogrel Resistance. 2004. https://doi.org/10.17615/xscg-ab86APA
Lau, W., Gurbel, P., Watkins, P., Neer, C., Hopp, A., Carville, D., Guyer, K., Tait, A., & Bates, E. (2004). Contribution of Hepatic Cytochrome P450 3A4 Metabolic Activity to the Phenomenon of Clopidogrel Resistance. https://doi.org/10.17615/xscg-ab86Chicago
Lau, Wei C., Paul A Gurbel, Paul Watkins, Charlene J Neer, Amy S Hopp, David G.M Carville, Kirk E Guyer et al. 2004. Contribution of Hepatic Cytochrome P450 3a4 Metabolic Activity to the Phenomenon of Clopidogrel Resistance. https://doi.org/10.17615/xscg-ab86- Creator
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Lau, Wei C.
- Other Affiliation: Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan
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Gurbel, Paul A.
- Other Affiliation: Sinai Center for Thrombosis Research, Sinai Hospital of Baltimore, Baltimore, Maryland
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Watkins, Paul
- Affiliation: School of Medicine, Department of Medicine, Division of General Medicine and Clinical Epidemiology
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Neer, Charlene J.
- Other Affiliation: Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan
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Hopp, Amy S.
- Other Affiliation: Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan
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Carville, David G.M.
- Other Affiliation: Division of Thrombosis, Department of Chemistry, Indiana University, South Bend, Indiana
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Guyer, Kirk E.
- Other Affiliation: Division of Thrombosis, Department of Chemistry, Indiana University, South Bend, Indiana
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Tait, Alan R.
- Other Affiliation: Department of Anesthesiology, University of Michigan, Ann Arbor, Michigan
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Bates, Eric R.
- Other Affiliation: Division of Cardiovascular Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
- 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 μmol/L)–induced platelet aggregation of less than 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.
- Date of publication
- 2004
- Keyword
- DOI
- Identifier
- 2-s2.0-1642453779
- https://doi.org/10.1161/01.CIR.0000112378.09325.F9
- Related resource URL
- Resource type
- Article
- Rights statement
- In Copyright
- Journal title
- Circulation
- Journal volume
- 109
- Journal issue
- 2
- Page start
- 166
- Page end
- 171
- Language
- English
- Version
- Postprint
- ISSN
- 0009-7322
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