Clopidogrel provides less platelet inhibition than expected in approximately 25 to 30 percent of patients. The pharmacogenetic mechanism responsible for this interindividual variability is:

• A Polymorphism of glycoprotein IIb/IIIa reducing final common pathway aggregation
• B Overexpression of P-glycoprotein increasing renal clearance of the parent drug
• C Gain-of-function polymorphism of the platelet P2Y12 receptor causing receptor resistance
• D Loss-of-function polymorphism of CYP2C19 reducing conversion to the active thiol metabolite ✓

Explanation

Clopidogrel is a prodrug requiring two-step hepatic oxidation by CYP2C19 (with contributions from CYP3D4 and others) to generate its active thiol metabolite. CYP2C19*2 and *3 loss-of-function alleles classify carriers as intermediate or poor metabolisers, producing diminished antiplatelet effect and higher rates of stent thrombosis and cardiovascular events. Ticagrelor and prasugrel bypass this variability, which partly underlies their superiority in trials. P2Y12 resistance is not the established mechanism for clopidogrel hyporesponsiveness.

Reference: Katzung's Basic and Clinical Pharmacology, 16th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.