A 28-year-old woman with bipolar disorder is started on lamotrigine. Valproate is added for better mood control. The dose of lamotrigine must be REDUCED by 50% because valproate:
- A Induces CYP3A4, accelerating lamotrigine clearance
- B Displaces lamotrigine from plasma proteins, increasing free drug levels
- C Inhibits UGT1A4-mediated glucuronidation of lamotrigine, doubling its half-life ✓
- D Alkalinises urine, reducing renal clearance of lamotrigine
Correct answer: C. Inhibits UGT1A4-mediated glucuronidation of lamotrigine, doubling its half-life
Explanation
Lamotrigine is primarily metabolised by UGT1A4 (glucuronidation) in the liver. Valproate is a potent inhibitor of UGT1A4, reducing lamotrigine clearance and approximately doubling its plasma half-life (from ~25 h to ~60 h). Failure to halve the lamotrigine dose leads to toxic levels and risks Stevens-Johnson syndrome. Valproate is not a CYP3A4 inducer, and protein displacement is not the primary mechanism.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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