Anticonvulsant activity of metabolites of valproic acid

Eight metabolites of valproic acid (VPA), i.e. 2-en-VPA, 3-hydroxy VPA, 3-keto-VPA, 4-en-VPA, 5-hydroxy-VPA, 2-n-propylglutaric acid, 3-en-VPA, and 4-hydroxy-VPA, were examined for their effects on the thresholds for the maximal electroconvulsion and the pentetrazole convulsion in mice. All metabolites gave rise to significant threshold elevations but were less potent than VPA itself. Among the metabolites studied, the unsaturated compounds 2-en-VPA and 4-en-VPA were most active showing 50 to 90% of the potency of VPA. Taking the different anticonvulsant potencies of VPA and its metabolites into consideration, VPA seems responsible for more than 80% of the antiepileptic effect during chronic therapy in man.