Clopidogrel is a prodrug requiring hepatic conversion. Which enzyme is primarily responsible for its activation, and what is the pharmacological consequence in CYP2C19 poor metabolisers?

• A CYP3A4; poor metabolisers generate excess active metabolite, causing bleeding
• B CYP2D6; poor metabolisers show no significant difference in anti-platelet efficacy
• C CYP2C19; poor metabolisers generate insufficient active thiol metabolite, resulting in reduced platelet P2Y12 inhibition and higher cardiovascular event rates ✓
• D CYP1A2; poor metabolisers require dose reduction to avoid GI haemorrhage

Explanation

Clopidogrel undergoes a two-step hepatic activation: first by CYP1A2/CYP2B6 to an intermediate, then by CYP2C19 to the active thiol metabolite that irreversibly blocks the platelet P2Y12 ADP receptor. CYP2C19 loss-of-function alleles (*2, *3) reduce active metabolite formation, resulting in diminished platelet inhibition and clinically increased rates of major adverse cardiovascular events (especially stent thrombosis) in poor metabolisers. The FDA mandates a boxed warning about this pharmacogenomic limitation; prasugrel and ticagrelor are alternatives not requiring CYP2C19 activation.

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

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