Clopidogrel is a prodrug requiring activation. Which enzyme is primarily responsible for its conversion to the active thiol metabolite?

• A CYP3A4
• B CYP2D6
• C Paraoxonase-1 (PON1)
• D CYP2C19 ✓

Explanation

Clopidogrel is a thienopyridine prodrug that undergoes two-step hepatic bioactivation. The first step is mediated by CYP1A2 and CYP2C19 (an intermediate thiolactone), and the crucial second oxidation step to the active thiol metabolite is predominantly catalyzed by CYP2C19. Loss-of-function polymorphisms in CYP2C19 (CYP2C19*2, *3 alleles)—present in ~30% of Asian patients—reduce active metabolite formation, resulting in inadequate platelet inhibition and increased cardiovascular events. This is the basis for CYP2C19 genotyping guidance. Prasugrel and ticagrelor were developed to overcome this polymorphism-related variability.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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