TIME-COURSE OF ALPHA-FLUORINATED VALPROIC ACID IN MOUSE-BRAIN AND SERUM AND ITS EFFECT ON SYNAPTOSOMAL GAMMA-AMINOBUTYRIC-ACID LEVELS IN COMPARISON TO VALPROIC ACID

To prevent the hepatotoxicity of valproic acid (VPA), a fluorine subst ituent was introduced at the alpha-position to eliminate the formation of putative toxic metabolites through mitochondrial beta-oxidation. A lthough the alpha-fluorinated VPA analogue (alpha-fluoro VPA) is more acidic (pK(a) = 3.55) than VPA (pK(a) = 4.80), the lipophilicity of th ese two compounds, as determined by their log P values, were similar w hen compared at pH 2.5. Brain, serum and urine samples were prepared f rom mature male CD-1 mice treated with either alpha-fluoro VPA or VPA for quantitation of drug concentrations. Brain synaptosomes were isola ted to determine gamma-aminobutyric acid levels, After equivalent dose s of 0.83 mmol/kg, alpha-fluoro VPA was characterized by its slower ac cess into mouse brain, compared to VPA. The peak concentration of alph a-fluoro VPA in mouse brain was achieved 45 min later than in the seru m, whereas the peak brain level of VPA coincided with the peak serum l evel occurring within 15 min. Simultaneous curve fitting of both brain and serum drug concentrations using a two-compartment model indicated that alpha-fluoro VPA, like VPA, may be asymmetrically transported ac ross the blood-brain-barrier. This property of alpha-fluoro VPA was al so reflected in its low brain-to-serum concentration ratio of 0.09 at the peak brain drug concentration (0.16 for VPA). The primary beta-oxi dation metabolite of VPA was not found in the serum and urine of mice treated with alpha-fluoro VPA. Although the glucuronide was a major me tabolite of VPA (28.5% of the dose), alpha-fluoro VPA was observed to conjugate extensively with L-glutamine (33.3% of the dose). alpha-Fluo ro VPA appeared to persist in the general circulation, which, in turn, may contribute to the apparent slow elimination of the drug from the brain. The fluorinated compound was demonstrated to have anticonvulsan t activity in the 1,5-pentamethylenetetrazole seizure test and to be c apable of increasing brain synaptic gamma-aminobutyric acid, the ED50 being 1.70 mmol/kg. These results suggest that alpha-fluoro VPA has po tential as a new anticonvulsant drug.