Polymorphisms of genes related to phase-I metabolic enzymes affecting the clinical efficacy and safety of clopidogrel treatment

ABSTRACT

Introduction: Clopidogrel is an antiplatelet medication described as a prodrug, which cannot exert the antiplatelet effect until being biotransformed to the active metabolite. It is commonly used to reduce the risk of blood coagulation in patients diagnosed with acute coronary syndrome, or ischemic stroke.

Area covered: We reviewed published articles in PubMed and Google Scholar that focused on the mutations of CYP2C19, CYP3A4, CYP2C9, CYP2B6, and CYP1A2 genes related to clopidogrel clinical efficacy and safety.

Expert opinion: Based on current pharmacogenetic studies, patients carrying CYP2C19*2, CYP2C19*3, CYP2C9*3, and CYP2B6*5 alleles may not respond to clopidogrel due to poor platelet inhibition efficacy revealed among them. In contrast, carriers of CYP2C19*17, CYP3A4*1G, and CYP1A2*1C alleles showed a more significant antiplatelet effect in clopidogrel users and expected to have a protective role as a genetic factor against cardiovascular events. Genotyping for either CYP2C19, CYP3A4, CYP2C9, CYP2B6, or CYP1A2 variants is not recommended when considering clopidogrel treatment for patients, as some trials showed specific non-genetic factors (e.g. age and diabetes) that could affect clopidogrel responsiveness. Instead, platelets inhibition tests could be used as predictors of the clinical efficacy of clopidogrel treatment. Other P2Y12 receptor inhibitors should be considered as alternative medications.

KEYWORDS:

• Clopidogrel
• gene polymorphism
• antiplatelets activity
• phase-I metabolism
• pharmacogenetics

Article highlights

• Carriers of the CYP2C19*17 allele have better clinical efficacy after using clopidogrel.

• CYP3A4*1B allele had no significant effect on the antiplatelet activity of clopidogrel.

• Carriers CYP2C9*2 or CYP2C9*3 alleles were not responding to clopidogrel treatment.

• No significant deviation of PRU among patients carrying CYP2B6*6 allele compared to non-carriers.

• Smokers carrying of CYP1A2*1F/*1F genotype had a higher risk of not responding to clopidogrel.

• Clopidogrel responsiveness was significantly high among patients carrying CYP1A2*1C allele

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Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.