A patient on warfarin for AF is started on rifampicin for tuberculosis. The INR drops from 2.5 to 1.2 after two weeks. The molecular mechanism of this interaction is:
- A Rifampicin activates pregnane X receptor (PXR), which upregulates CYP2C9 and CYP3A4 transcription, accelerating warfarin hydroxylation and reducing its anticoagulant levels ✓
- B Rifampicin chelates warfarin in the gut, preventing its absorption
- C Rifampicin activates vitamin K epoxide reductase (VKORC1), reversing warfarin's anticoagulant effect
- D Rifampicin displaces warfarin from plasma albumin, increasing free warfarin clearance
Explanation
Rifampicin is the most potent inducer of hepatic CYP450 enzymes clinically available. It activates PXR (pregnane X receptor, also known as nuclear receptor NR1I2), a ligand-activated transcription factor that drives expression of CYP2C9 (which hydroxylates S-warfarin, the more potent enantiomer), CYP3A4, UGTs, and P-glycoprotein. The net effect is 5–10-fold acceleration of warfarin metabolism, necessitating 2–5× dose increases to maintain therapeutic INR. Importantly, when rifampicin is stopped, CYP induction resolves within 2–3 weeks and warfarin doses must be reduced urgently to prevent over-anticoagulation and bleeding.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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