A patient taking warfarin is prescribed rifampicin for tuberculosis treatment. The warfarin anticoagulant effect is markedly reduced. The biochemical mechanism is:

• A Rifampicin chelates warfarin in the gut preventing absorption
• B Rifampicin competitively inhibits warfarin binding to albumin, increasing free warfarin excretion
• C Rifampicin induces CYP2C9 (and CYP3A4) via PXR nuclear receptor activation, accelerating warfarin metabolism ✓
• D Rifampicin induces vitamin K epoxide reductase, counteracting warfarin's mechanism

Explanation

Rifampicin is a potent inducer of nuclear receptors PXR (pregnane X receptor) and CAR (constitutive androstane receptor). PXR/CAR activation transcriptionally induces multiple CYP450 enzymes, particularly CYP2C9 and CYP3A4, which are the primary enzymes metabolising S-warfarin (the pharmacologically active enantiomer) and R-warfarin respectively. Increased CYP2C9 activity dramatically accelerates warfarin hydroxylation and clearance, reducing its anticoagulant effect within days. Warfarin doses may need to be doubled or tripled during rifampicin co-administration, with careful INR monitoring. Vitamin K epoxide reductase induction would also reduce warfarin efficacy, but this is not the established mechanism of rifampicin interaction.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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Written and medically reviewed by the StethoPrep medical team.