A 35-year-old man with a 10-year history of focal onset epilepsy with secondary generalization, on carbamazepine 800 mg/day, develops breakthrough seizures. He is also started on valproate. Two weeks later he develops diplopia, ataxia, and drowsiness. Serum carbamazepine level is 18 μg/mL (therapeutic 4–12 μg/mL). What is the pharmacokinetic explanation?

• A Valproate inhibits carbamazepine metabolism via CYP3A4 inhibition
• B Carbamazepine induces valproate metabolism causing valproate toxicity
• C Valproate inhibits epoxide hydrolase, increasing carbamazepine-10,11-epoxide levels ✓
• D Combined GABA enhancement causing additive CNS depression

Explanation

Carbamazepine is metabolized to carbamazepine-10,11-epoxide (CBZ-E), which is the active toxic metabolite, by CYP3A4. CBZ-E is then inactivated by epoxide hydrolase. Valproate strongly inhibits epoxide hydrolase (not CYP3A4 directly), leading to accumulation of the active epoxide metabolite causing carbamazepine toxicity (diplopia, ataxia, drowsiness) even at standard carbamazepine doses. This is a clinically important pharmacokinetic drug interaction distinct from the autoinduction of carbamazepine's own metabolism through CYP3A4.

Reference: Harrison's Principles of Internal Medicine, 21st ed.

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