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Effects of polytherapy with phenytoin, carbamazepine, and stiripentol on formation of 4‐ene‐valproate, a hepatotoxic metabolite of valproic acid
Author(s) -
Levy René H,
Rettenmeier Albert W,
Anderson Gail D,
Wilensky Alan J,
Friel Patrick N,
Baillie Thomas A,
Acheampong Andrew,
Tor Jacques,
Guyot Martine,
Loiseau Pierre
Publication year - 1990
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.1990.144
Subject(s) - valproic acid , carbamazepine , metabolite , phenytoin , chemistry , pharmacology , anticonvulsant , probenecid , medicine , epilepsy , biochemistry , psychiatry
The incidence of valproic acid hepatotoxicity has been reported to increase in patients who are receiving polytherapy. A minor valproic acid metabolite, 2‐propyl‐4‐pentenoic acid (4‐ene‐VPA), formed by a cytochrome P450‐mediated reaction, has been shown to be a potent inducer of microvesicular steatosis in rats. This study tested the hypothesis that formation of 4‐ene‐VPA would be increased in patients taking valproic acid with carbamazepine or with phenytoin but decreased with coadministration of an inhibitor of cytochrome P450 (the antiepileptic drug stiripentol in 300 to 1200 mg daily doses) in healthy subjects. Blood and urine samples in the studies were collected during a dosing interval at steady state. Valproic acid was assayed in plasma by capillary gas chromatography; valproic acid and 15 metabolites were measured in urine by gas chromatography/mass spectrometry. The formation clearance (CL f ) of 4‐ene‐VPA was increased twofold in the valproic acid‐carbamazepine and valproic acid‐phenytoin groups. In the valproic acid/stiripentol studies, the CL f of 4‐ene‐VPA decreased by 32% in the 1200 mg/day stiripentol study. Similar findings were obtained at 600 and 300 mg/day stiripentol. These findings provide evidence supporting a role for cytochrome P450 in the formation of the hepatotoxic metabolite, 4‐ene‐VPA, in humans. The increased formation of 4‐ene‐VPA associated with carbamazepine and phenytoin is striking in relation to the epidemiologic finding of increased incidence of valproic acid–related hepatotoxicity during polytherapy with P450 inducers. Clinical Pharmacology and Therapeutics (1990) 48, 225–235; doi: 10.1038/clpt.1990.144