Clopidogrel is an antithrombotic drug. Chemically, it is a prodrug that requires hepatic biotransformation to yield an active metabolite that selectively and irreversibly inhibits platelet aggregation for approximately 10 days by inhibiting the platelet P2RY12 receptor. Clopidogrel is commonly prescribed for acute coronary syndromes (ACS) and/or after PCI (percutaneous coronary intervention).

The conversion of clopidogrel to its active or functional metabolite requires the involvement of a class of enzymes called CYPs cytochromes. Although several different cytochromes are involved, it has been widely described which genetic polymorphisms present in CYP2C19 are associated with altered pharmacodynamic and pharmacokinetic response.

The CYP2C19 gene is highly polymorphic, with more than 25 different alleles known (http://www.cypalleles.ki.se/cyp2c19.htm). The wild-type CYP2C19*1 allele is associated with CYP2C19-mediated functional metabolism. The most common CYP2C19 loss-of-function (LoF) allele is CYP2C19*2 (c.681G>A, denoted rs4244285 in clinical databases), with allele frequencies of ~ 15% in Caucasians and Africans, and 29-35% in Asians. Other CYP2C19 variant alleles with reduced or absent enzyme activity (e.g. CYP2C19*3-*8) have been identified; however, their frequencies are typically less than 1%, with the exception of CYP2C19*3 (c.636G>A; rs4986893) in Asians (with an allele frequency of 2-9%).

CYP2C19 LoF alleles hinder the formation of active metabolites, resulting in reduced platelet inhibition. Several studies have shown that CYP2C19*2 heterozygotes and homozygotes have lower clopidogrel active metabolite concentration and thus higher on-treatment platelet aggregation compared to homozygotes*1. Furthermore, CYP2C19 loss-of-function alleles confer an increased risk of serious cardiovascular (CV) adverse events among clopidogrel-treated patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI).

In the case of CYP2C19*1/*2 or CYP2C19*1/*3 heterozygotes (e.g., CYP2C19*1/*2 or CYP2C19*1/*3), the antiplatelet response is intermediate in efficacy between normal or wild-type homozygotes (CYP2C19*1/*1) and LoF homozygotes or compound heterozygotes (e.g., CYP2C19*1/*1) and LoF homozygotes or compound heterozygotes (e.g., CYP2C19*2/*2/*3), CYP2C19*2/*2 (homozygous) or CYP2C19*2/*3 (compound heterozygous, but for practical purposes behaves as homozygous).cotes to behave as homozygous).

Based on CYP2C19 genotypes, individuals are typically classified as extensive metabolizers (CYP2C19*1/ CYP2C19*1 MSs), intermediate metabolizers (IMs, i.e., *1/*2 and *1/*3), or poor metabolizers (PM, i.e., *2/*2 and *2/*3). In contrast, the common CYP2C19*17 allele (c.3402C>T, rs11188072) results in increased activity (gain-of-function allele, GoF) as a consequence of enhanced transcription, with average multiethnic allele frequencies of approximately 3-21%. Therefore, individuals who carry one or two copies of this allele can be categorized as ultrafast metabolizers (e.g., CYP2C19*1/*17 or CYP2C19*17/*17). Ultrarapid metabolizers will have a lower dose, which should be strictly adhered to, as the CYP2C19*17 allele may be associated with an increased risk of bleeding.

Regarding the CYP2C19*17 gain-of-function allele cannot fully compensate for the loss of function that occurs when the CYP2C19*2 variant is present, compound heterozygous individuals with CYP2C19*2/*17 genotype are classified as intermediate metabolizers (IM).

Of note is the study of the CYP2C19*10 allele (rs6413438), which is a decreased function allele and is currently classified as "probable IM". The frequency of CYP2C19*10 in African Americans (0.8%), Hispanics (0.25%), and whites (0%) is relatively low. However, the impact of this allele is important because in addition to its effect on drug metabolism, it also affects genotyping of the CY2C19*2 SNP, resulting in misclassification of CYP2C19*10/*2 as CYP2C19*2/*2.

Following FDA and CIPC ("European Clinical Pharmacogenetics Implementation Consortium") guidelines, we can conclude that: Patients with IM genotype (i.e., *1/*2 or *1/*3 or *2/*17) should be prescribed an alternative antiplatelet therapy (such as prasugrel or ticagrelor) or decrease the drug dose if there are no contraindications, and for patients with PM genotype a change in medication (prasugrel or ticagrelor) is strongly recommended.

Due to the high variability in the efficacy of clopidrogrel and the frequency of occurrence of adverse effects, the FDA recommends genotyping of patients prior to prescription and dose adjustment.

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