CYP2C19 poor metabolisers (PMs) on clopidogrel therapy have significantly higher rates of adverse cardiovascular events compared to extensive metabolisers (EMs) because:

• A PMs accumulate clopidogrel's parent compound, which competitively inhibits CYP3A4 and increases adverse drug interactions
• B PMs have increased expression of P-glycoprotein in the gut, reducing clopidogrel bioavailability
• C PMs cannot convert clopidogrel prodrug to its active thiol metabolite, resulting in inadequate P2Y12 inhibition and reduced antiplatelet effect ✓
• D PMs have higher plasma fibrinogen levels due to CYP2C19-dependent fibrinogen degradation

Explanation

Clopidogrel undergoes two-step hepatic bioactivation: intestinal CYP3A4 converts the prodrug to a 2-oxo-clopidogrel intermediate, and CYP2C19 converts this to the active thiol metabolite that irreversibly inhibits P2Y12. CYP2C19 poor metabolisers (∼30% of south Asians, 15–20% of East Asians) generate significantly less active metabolite, resulting in reduced platelet inhibition and increased risk of stent thrombosis. FDA has a boxed warning for clopidogrel regarding CYP2C19 poor metaboliser status, and ticagrelor (which does not require CYP2C19 bioactivation) is preferred in such patients.

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

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Written and medically reviewed by the StethoPrep medical team.