Studies on the biotransformation in the perfused rat liver of 2-n-propyl-4-pentenoic acid, a metabolite of the antiepileptic drug valproic acid. Evidence for the formation of chemically reactive intermediates.

The metabolism of 2-n-propyl-4-pentenoic acid (delta 4-VPA), a putative toxic biotransformation product of valproic acid (VPA), was examined in the isolated perfused rat liver. Metabolites excreted into perfusion medium and bile were characterized by GLC and GC/MS techniques and their identities were verified by synthesis. A total of eight metabolites was detected, the structures of which could be best accounted for by initial oxidation reactions catalyzed by either cytochrome P-450 or the fatty acid beta-oxidation complex. Evidence was obtained which indicates that metabolism of delta 4-VPA by each of these enzyme systems can lead to the generation of chemically reactive intermediates which may contribute to the hepatotoxic properties of VPA.