Valproic acid: metabolite concentrations in plasma and brain, anticonvulsant activity, and effects on GABA metabolism during subacute treatment in mice.

Mice were continuously treated with valproic acid (VPA) via the drinking water for period from 1 to 12 days. The daily drug intake varied between 500 and 580 mg/kg. However, due to the rapid elimination of VPA in this species average plasma concentrations of only 3-4 micrograms/ml VPA were present at 8:30 a.m., the time chosen for determinations. In the brain, VPA levels were about 10% of those in plasma. In regard to VPA metabolism the products of beta-oxidation 2-en-VPA 2-propyl-2-pentenoic acid) and 3-keto-VPA (2-propyl-3-oxopentanoic acid) proved to be the main metabolites in plasma although other (minor) metabolites of VPA were also present. The only metabolite of VPA detected in the brain was 2-en-VPA. VPA medication caused a significant increase in the threshold for electroconvulsions which was associated with a slight increment of brain GABA levels. The activity of glutamic acid decarboxylase was significantly elevated whereas GABA aminotransferase was not affected. After withdrawal of VPA, a delayed effect on seizure threshold was observed which extended to time periods where VPA could no longer be detected in the brain, but 2-en-VPA was still present.