Clopidogrel is a prodrug requiring CYP2C19 activation. A patient on clopidogrel and omeprazole post-coronary stent placement has a recurrent NSTEMI. The most pharmacokinetically appropriate explanation is:

• A Omeprazole chelates clopidogrel in the gastric lumen, reducing its absorption
• B Omeprazole induces P-glycoprotein, increasing efflux of active clopidogrel metabolite back into the intestinal lumen
• C Omeprazole raises gastric pH, reducing the ionisation of clopidogrel and preventing absorption
• D Omeprazole is a competitive inhibitor of CYP2C19, reducing conversion of clopidogrel to its active thiol metabolite ✓

Explanation

Clopidogrel requires two-step hepatic oxidation by CYP2C19 (and CYP1A2/CYP3A4) to generate its active thiol metabolite, which irreversibly blocks the platelet P2Y12 ADP receptor. Omeprazole (and esomeprazole) are potent CYP2C19 inhibitors; co-administration reduces formation of the active metabolite by approximately 40–50%, leading to reduced antiplatelet efficacy (stent thrombosis risk). Pantoprazole has the least CYP2C19 inhibition and is preferred with clopidogrel if a PPI is needed.

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

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Written and medically reviewed by the StethoPrep medical team.