A patient on phenytoin for generalised tonic-clonic seizures is started on rifampicin for pulmonary tuberculosis. What pharmacokinetic consequence is expected?

• A Rifampicin inhibits CYP2C9, raising phenytoin levels and causing toxicity
• B Rifampicin displaces phenytoin from plasma proteins, causing acute toxicity then normal levels
• C Rifampicin induces CYP2C9/3A4, reducing phenytoin levels and risking seizure breakthrough ✓
• D Phenytoin inhibits rifampicin hepatic uptake, raising rifampicin levels

Explanation

Rifampicin is a potent broad-spectrum inducer of CYP enzymes including CYP2C9 (the main enzyme metabolising phenytoin) and CYP3A4. This induction accelerates phenytoin metabolism, reducing its plasma concentrations by 20–40%, which can lead to seizure breakthrough. Clinicians must monitor phenytoin levels closely and increase the dose if needed when rifampicin is co-administered. The reverse is that phenytoin (an inducer itself) can reduce rifampicin levels slightly, but the dominant clinically important interaction is rifampicin lowering phenytoin.

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

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Written and medically reviewed by the StethoPrep medical team.