Clopidogrel requires bioactivation to its thienopyridine-active metabolite. A patient homozygous for the CYP2C19*2 loss-of-function allele is started on clopidogrel after coronary stent placement. The clinical implication is:

• A The patient will experience excessive bleeding because the active metabolite accumulates due to reduced CYP2C19 metabolism
• B Clopidogrel will fail to provide adequate antiplatelet effect; platelet reactivity remains high, increasing stent thrombosis risk ✓
• C CYP2C19*2 affects the third oxidative step; the first two steps produce a partially active metabolite providing 60% of normal antiplatelet effect
• D Proton pump inhibitors overcome CYP2C19*2 inhibition by providing alternative metabolic activation of clopidogrel

Explanation

Clopidogrel is an irreversible P2Y12 ADP receptor antagonist prodrug requiring two-step hepatic oxidation: CYP1A2/CYP2C19 (step 1) then CYP2C19/CYP3A4 (step 2) to generate the active thiol metabolite. CYP2C19*2 is the most common loss-of-function allele (seen in ~15% Caucasians, 29–35% Asians). *2/*2 homozygotes produce negligible active metabolite, resulting in high on-treatment platelet reactivity (HTPR) and a 2–3× increased risk of major adverse cardiovascular events (MACE) including stent thrombosis. FDA Black Box Warning: test for CYP2C19 status; consider alternative P2Y12 inhibitors (prasugrel, ticagrelor — not CYP2C19 dependent) in poor metabolizers.

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

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