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Pharmacogenomics of clopidogrel: evidence and perspectives

Tong Yin1, Toshiyuki Miyata

  • 1Institute of Geriatric Cardiology, General Hospital of People's Liberation Army, Beijing, China.

Thrombosis Research
|May 20, 2011
PubMed

Insights

Genetic variations in CYP2C19 significantly impact clopidogrel effectiveness, influencing antiplatelet response and cardiac event risk. Further research is needed to validate CYP2C19 genotyping for personalized clopidogrel therapy.

Area of Science:

  • Pharmacogenomics
  • Cardiovascular Medicine
  • Drug Metabolism

Background:

  • Clopidogrel is a primary oral antiplatelet agent for preventing ischemic events post-acute coronary syndromes or stent placement.
  • Significant interindividual variability exists in clopidogrel's antiplatelet effects, with reduced response linked to increased ischemic complication risk.

Purpose of the Study:

  • To review the impact of genetic polymorphisms, particularly in cytochrome P450 (CYP) 2C19, on clopidogrel responsiveness.
  • To discuss the implications of CYP2C19 genotype on adverse cardiac events and FDA recommendations.
  • To highlight the emerging role of paraoxonase-1 (PON1) in clopidogrel bioactivation and the need for further genetic research.

Main Methods:

  • Review of pharmacogenomic studies, including candidate-gene and genome-wide association studies.
  • Analysis of prospective studies examining the association between CYP2C19 polymorphisms and clopidogrel response.
  • Inclusion of findings from recent trials identifying PON1 as a key enzyme in clopidogrel metabolism.

Main Results:

  • CYP2C19 reduced-function alleles are associated with decreased clopidogrel responsiveness and increased risk of adverse cardiac events.
  • Conflicting results exist, with one large randomized study not replicating these findings.
  • The Q192R polymorphism in PON1 influences clopidogrel's active metabolite formation and clinical activity.

Conclusions:

  • CYP2C19 genotype influences clopidogrel efficacy, prompting FDA warnings and suggestions for dose adjustment or alternative therapies in high-risk individuals.
  • Current evidence is insufficient to recommend routine CYP2C19 genotyping for guiding clopidogrel therapy; prospective trials are needed.
  • Further investigation into CYP2C19, PON1, and other genetic variants' influence on clopidogrel across diverse populations is warranted.

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