A patient on phenytoin for seizures requires initiation of warfarin for atrial fibrillation. Two weeks later, the patient is found to have subtherapeutic INR despite adequate warfarin dosing. Subsequently, the patient is switched off phenytoin to levetiracetam. One week later, the patient presents with massive GI bleed and INR of 8. What is the mechanism?

• A Phenytoin induced CYP2C9 which metabolized warfarin faster; stopping phenytoin allowed warfarin levels to rise ✓
• B Levetiracetam directly inhibits vitamin K epoxide reductase, potentiating warfarin's anticoagulant effect
• C Phenytoin competitively displaced warfarin from plasma proteins; stopping phenytoin freed warfarin, increasing free drug levels
• D Levetiracetam inhibits CYP2C9, directly increasing warfarin concentration

Explanation

Phenytoin is a potent inducer of CYP2C9 and CYP3A4 (via PXR-mediated transcriptional induction), which are the primary enzymes metabolizing S-warfarin (the more potent enantiomer) and R-warfarin respectively. During co-administration, higher warfarin doses are required to maintain therapeutic INR. When phenytoin is abruptly discontinued, CYP2C9/3A4 activity gradually returns to baseline (enzyme de-induction over 2-3 weeks), reducing warfarin clearance and causing warfarin accumulation. Levetiracetam has no CYP-inducing or CYP-inhibiting activity. This is a classic drug interaction scenario illustrating enzyme induction and de-induction kinetics.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.