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

To investigate the regional distribution of valproic acid (VPA) and 10 of i ts metabolites in the rat brain, the animals were treated with 300 mg/kg/da y VPA i.p. on a 3 times daily dose regimen for 5 days, and the concentratio ns of the compounds in serum and 15 brain regions were measured. 2-(n-propy l)-(Z)-2-pentenoic acid [(Z)-2-en], a VPA metabolite expected to possess ne urotoxic potency in humans, was determined in brain tissue for the first ti me. The brain/serum concentration ratio of (Z)-2-en was found to be about 1 4-fold higher than the ratio for its (E)-isomer, thereby demonstrating the influence of the double-bond configuration in the unsaturated metabolites o n their ability to penetrate into the central nervous system. The concentra tions of VPA and its metabolites in the brain regions were compared to c(ho m), the calculated concentration for an assumed homogeneous distribution. T he parent drug and its metabolites exhibited individual distribution patter ns with varying degrees of inhomogeneity. Elevated metabolite concentration s were found especially in the motorium and the medulla oblongata. Decrease d concentrations of VPA and several metabolites were found in the visual co rtex.