Vitamin K-dependent carboxylation converts glutamic acid (Glu) residues to gamma-carboxyglutamic acid (Gla) residues in clotting factors. This reaction requires reduced vitamin K (KH2). After carboxylation, KH2 is oxidized to vitamin K 2,3-epoxide. Warfarin inhibits vitamin K epoxide reductase (VKOR). In a patient on stable warfarin with INR 2.5, which newly added drug would MOST predictably raise INR by pharmacokinetic interaction?
- A Rifampicin (inducer of CYP2C9)
- B Cholestyramine (bile acid sequestrant)
- C Fluconazole (inhibitor of CYP2C9) ✓
- D Phenytoin (inducer of CYP2C9 and CYP3A4)
Explanation
Warfarin (specifically S-warfarin, the more potent enantiomer) is primarily metabolized by CYP2C9. Fluconazole is a potent inhibitor of CYP2C9, significantly reducing S-warfarin clearance and raising plasma warfarin levels, which intensifies anticoagulation and increases INR. Rifampicin and phenytoin are CYP2C9 inducers, increasing warfarin metabolism and reducing INR (sub-therapeutic anticoagulation risk). Cholestyramine binds warfarin in the gut, reducing its absorption and lowering INR. This pharmacokinetic interaction through CYP2C9 is clinically highly significant — fluconazole is among the drugs most commonly implicated in warfarin-related bleeding complications.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
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Written and medically reviewed by the StethoPrep medical team.