Distribution of valproic acid and its metabolites in various brain areas of dogs and rats after acute and prolonged treatment.

Concentrations of valproic acid (VPA) and various metabolites were determined in plasma, cerebrospinal fluid and discrete brain areas in dogs after acute treatment with VPA as well as in rats during prolonged constant-rate application of the drug via osmotic minipumps. Highly sensitive gas chromatograph-mass spectrometer-computer methods were used for drug and metabolite analysis. Of several VPA metabolites present in plasma of dogs and rats only one could be found in the brain of both species, 2-propyl-2-pentenoic acid (2-en-VPA). Distribution of VPA and 2-en-VPA in the brain was rather homogenous, but during prolonged treatment accumulation of 2-en-VPA was found to occur in some brain regions. Determination of anticonvulsant potency of 2-en-VPA in mice indicated that the compound is about 1.3 times more potent than the parent drug when calculation is based on whole-brain concentrations. Administration of 2-en-VPA in a dog showed that pharmacokinetics of this substance are similar to those of VPA, although plasma protein binding of 2-en-VPA (97%) is much higher than of VPA. The results suggest that 2-en-VPA may contribute significantly to the anticonvulsant effect of (chronic) treatment with VPA.