A 40-year-old man taking valproate for epilepsy shows elevated serum ammonia with encephalopathy but near-normal liver enzymes. The most likely mechanism for this valproate-associated hyperammonemia is:
- A Inhibition of carbamoyl phosphate synthetase I (CPS-I) activity by valproate metabolites, impairing ureagenesis ✓
- B Hepatocellular necrosis causing urea cycle disruption
- C Renal tubular inhibition of ammonia excretion
- D Induction of glutaminase in skeletal muscle
Correct answer: A. Inhibition of carbamoyl phosphate synthetase I (CPS-I) activity by valproate metabolites, impairing ureagenesis
Explanation
Valproate and its metabolite (propionic acid derivatives) deplete mitochondrial acetyl-CoA and N-acetylglutamate (NAG), which is the obligate allosteric activator of CPS-I in the urea cycle. Reduced CPS-I activity impairs ammonia disposal, causing hyperammonemia even with normal liver enzymes—a distinct entity from valproate hepatotoxicity. This is treated by supplementing L-carnitine or N-acetylglutamate; arginine can also help. Hepatocellular necrosis presents with raised transaminases.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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