Valproate metabolites in the rat brain--regional distribution in various brain areas

To investigate the regional distribution of valproic acid (VPA) and 10 of its metabolites in the rat brain, the animals were treated with 300 mg/kg/day VPA i.p. on a 3 times daily dose regimen for 5 days, and the concentrations of the compounds in serum and 15 brain regions were measured. 2-(n-propyl)-(Z)-2-pentenoic acid [(Z)-2-en], a VPA metabolite expected to possess neurotoxic potency in humans, was determined in brain tissue for the first time. The brain/serum concentration ratio of (Z)-2-en was found to be about 14-fold higher than the ratio for its (E)-isomer, thereby demonstrating the influence of the double-bond configuration in the unsaturated metabolites on their ability to penetrate into the central nervous system. The concentrations of VPA and its metabolites in the brain regions were compared to c(hom), the calculated concentration for an assumed homogeneous distribution. The parent drug and its metabolites exhibited individual distribution patterns with varying degrees of inhomogeneity. Elevated metabolite concentrations were found especially in the motorium and the medulla oblongata. Decreased concentrations of VPA and several metabolites were found in the visual cortex.