A patient on valproate and lamotrigine develops severe rash and mucositis consistent with Stevens-Johnson syndrome. The pharmacokinetic interaction responsible is:
- A Lamotrigine induces CYP3A4 causing valproate accumulation
- B Valproate inhibits UGT1A4, the glucuronyl-transferase responsible for lamotrigine metabolism, doubling its half-life and increasing toxicity risk ✓
- C Valproate displaces lamotrigine from plasma proteins increasing free fraction
- D Both drugs compete for the same renal tubular transporter
Correct answer: B. Valproate inhibits UGT1A4, the glucuronyl-transferase responsible for lamotrigine metabolism, doubling its half-life and increasing toxicity risk
Explanation
Lamotrigine is primarily glucuronidated by UGT1A4 (and UGT2B7). Valproate is a potent inhibitor of UGT1A4, dramatically reducing lamotrigine clearance and approximately doubling its plasma half-life from ~25 hours to ~60 hours. This pharmacokinetic interaction increases lamotrigine exposure significantly, raising the risk of serious skin reactions (SJS/TEN). When valproate is co-prescribed, the lamotrigine starting dose must be halved and titration slowed. Options B, C, and D are pharmacokinetically inaccurate.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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Written and medically reviewed by the StethoPrep medical team.