A patient on rifampicin-based anti-TB therapy is also on warfarin for a prosthetic heart valve. After two weeks of starting rifampicin, his INR drops from 2.8 to 1.3 despite unchanged warfarin dose. The mechanism is:
- A Rifampicin chelates warfarin in the GI tract, reducing its absorption and bioavailability
- B Rifampicin competitively displaces warfarin from plasma albumin, increasing renal clearance of free warfarin
- C Rifampicin is a potent inducer of CYP2C9 and CYP3A4, markedly increasing warfarin metabolism and reducing its anticoagulant effect ✓
- D Rifampicin inhibits vitamin K epoxide reductase, increasing clotting factor synthesis and counteracting warfarin
Correct answer: C. Rifampicin is a potent inducer of CYP2C9 and CYP3A4, markedly increasing warfarin metabolism and reducing its anticoagulant effect
Explanation
Rifampicin is the most potent inducer of hepatic CYP450 enzymes (CYP2C9, CYP3A4) and P-glycoprotein. Warfarin (especially S-warfarin) is primarily metabolised by CYP2C9. Rifampicin induction dramatically increases warfarin clearance, requiring a 3-5 fold increase in warfarin dose to maintain therapeutic INR during therapy. On stopping rifampicin, induction wanes over 2-3 weeks and warfarin dose must be reduced to avoid dangerous over-anticoagulation. Rifampicin does not chelate warfarin or inhibit vitamin K reductase.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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