A 28-year-old woman with epilepsy is being initiated on lamotrigine. The dose is titrated slowly when given with valproate because valproate:

• A Inhibits glucuronidation of lamotrigine, markedly increasing its plasma half-life ✓
• B Induces CYP3A4, which metabolizes lamotrigine, reducing its levels
• C Competes with lamotrigine for renal tubular secretion, increasing lamotrigine levels
• D Displaces lamotrigine from plasma protein binding, causing toxicity

Explanation

Lamotrigine is primarily metabolized by UDP-glucuronosyltransferases (UGTs), particularly UGT1A4 and UGT2B7. Valproate inhibits these enzymes, causing a 2-fold increase in lamotrigine plasma half-life (from ~25 hours to ~60 hours) and doubling its AUC. This pharmacokinetic interaction necessitates starting lamotrigine at a lower dose and titrating more slowly when co-prescribed with valproate to avoid dose-related toxicity such as rash, dizziness, and (rarely) Stevens-Johnson syndrome. Carbamazepine and phenytoin, being CYP inducers, have the opposite effect—reducing lamotrigine levels.

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

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