A patient on phenytoin for epilepsy is started on rifampicin for tuberculosis. Two weeks later, his seizure frequency increases despite good adherence. What is the most likely pharmacokinetic explanation?

• A Rifampicin inhibits CYP2C9, reducing phenytoin metabolism
• B Rifampicin displaces phenytoin from plasma proteins, increasing free drug
• C Rifampicin reduces gastric pH, decreasing phenytoin absorption
• D Rifampicin induces hepatic CYP enzymes, increasing phenytoin clearance ✓

Explanation

Rifampicin is a potent broad-spectrum inducer of hepatic CYP450 enzymes including CYP1A2, 2C9, 2C19, 3A4, and P-glycoprotein. Induction increases phenytoin metabolism, lowering its plasma concentration and reducing seizure control. The effect manifests over 1-2 weeks as enzyme protein synthesis increases. Rifampicin does not inhibit CYP2C9; it induces it. Protein displacement would transiently increase, not decrease, phenytoin effect.

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

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