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Clopidogrel Resistance, CYP2C19 Genetic Testing

Clopidogrel (brand name Plavix) is an antiplatelet agent. Clopidogrel reduces the risk of myocardial infarction and stroke in patients with acute coronary syndrome, and in patients with atherosclerotic vascular disease (indicated by a recent myocardial infarction or stroke or established peripheral arterial disease). Clopidogrel is also indicated in combination with aspirin in patients undergoing percutaneous coronary interventions, e.g., the placement of a stent. Clopidogrel belongs to the second generation of thienopyridine antiplatelet agents.

Clopidogrel is given to treat or prevent further occurrences of arterial thrombosis, which occurs when a blood clot (thrombus) forms inside an artery. Often, arterial thrombosis is triggered in response to the rupturing of the atherosclerotic plaque lining the arterial wall. If the thrombus occludes the arterial lumen, the blood flow is reduced or stopped, resulting in ischemia. In the brain, thrombosis in the cerebral arteries can cause a transient ischemic attack or ischemic stroke. In the peripheral vessels, thrombosis can cause peripheral artery disease, and in the heart, thrombosis in the coronary arteries is a common cause of acute coronary syndrome. Platelet inhibitors such as clopidogrel interrupt the formation of the thrombus, which involves the rapid recruitment and activation of platelets.

The effectiveness of clopidogrel depends on its conversion to an active metabolite by CY2C19. Individuals who carry 2 non-functional copies of the CYP2C19 gene are classified as CYP2C19 poor metabolizers. They have no enzyme activity and cannot activate clopidogrel via the CYP2C19 pathway, which means the drug will have no effect.

The primary metabolism of many drugs is performed by the cytochrome P450 (CYP) enzymes, a group of enzymes localized in the microsomes of many tissues including the intestines and liver. One of these CYP enzymes, CYP2C19, participates in the metabolism of a wide variety of drugs, including the activation of the anticoagulant clopidogrel and the inactivation of citalopram.

Clopidogrel is an inactive prodrug that requires hepatic bioactivation via several cytochrome P450 enzymes, including CYP2C19. The active metabolite irreversibly inhibits the platelet ADP receptor, P2Y12. Several different alleles of CYP2C19 have been identified; depending on the allele present, laboratory demonstrations of the enzymatic activity of CYP2C19 can be normal, reduced, or increased.

The *1 allele is the normal copy that has full enzymatic activity. The *2 and *3 alleles are the most common variants and result in a complete loss of enzymatic activity. Consequently, carriers of the *2 and *3 alleles have reduced the formation of clopidogrel's active metabolite and demonstrate reduced clopidogrel-induced platelet inhibition. The prevalence of the *2 and *3 alleles vary by ethnicity. In Caucasians, Blacks, and Asians, the proportion of patients who carry at least one copy of *2 is 25%, 30%, and 40-50% respectively, while the proportion for *3 is < 1%, < 1%, and 7%, respectively. 

Finally, variant *17 is present in nearly 40% of Caucasians, Blacks, and Asians, and results in increased CYP2C19 activity, higher production of the active metabolite, and improved clopidogrel-induced platelet inhibition.

The ABCB1 gene encodes a transporter protein that is involved in the removal of drugs from the cells, including clopidogrel and other xenobiotics. Substitution at position 3435 C>T is synonymous and does not alter the amino acid sequence of the protein, (Ile1145Ile), but changes its substrate specificity. T allele carriers have an increased risk of adverse cardiovascular events (cardiac death, myocardial infarction) in the treatment of acute coronary syndrome or heart attack with clopidogrel.

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