Abstract

To prevent the hepatotoxicity of valproic acid (VPA), a fluorine substituent was introduced at the α-position to eliminate the formation of putative toxic metabolites through mitochondrial β-oxidation. Although the α-fluorinated VPA analogue (α-fluoro VPA) is more acidic (pK_a = 3.55) than VPA (pK_a = 4.80), the lipophilicity of these two compounds, as determined by their log P values, were similar when compared at pH 2.5. Brain, serum and urine samples were prepared from mature male CD-1 mice treated with either α-fluoro VPA or VPA for quantitation of drug concentrations. Brain synaptosomes were isolated to determine γ-aminobutyric acid levels. After equivalent doses of 0.83 mmol/kg, α-fluoro VPA was characterized by its slower access into mouse brain, compared to VPA. The peak concentration of α-fluoro VPA in mouse brain was achieved 45 min later than in the serum, whereas the peak brain level of VPA coincided with the peak serum level occurring within 15 min. Simultaneous curve fitting of both brain and serum drug concentrations using a two-compartment model indicated that α-fluoro VPA, like VPA, may be asymmetrically transported across the blood-brain-barrier. This property of α-fluoro VPA was also reflected in its low brain-to-serum concentration ratio of 0.09 at the peak brain drug concentration (0.16 for VPA). The primary β-oxidation metabolite of VPA was not found in the serum and urine of mice treated with α-fluoro VPA. Although the glucuronide was a major metabolite of VPA (28.5% of the dose), α-fluoro VPA was observed to conjugate extensively with l-glutamine (33.3% of the dose). α-Fluoro 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 anticonvulsant activity in the 1,5-pentamethylenetetrazole seizure test and to be capable of increasing brain synaptic γ-aminobutyric acid, the ED₅₀ being 1.70 mmol/kg. These results suggest that α-fluoro VPA has potential as a new anticonvulsant drug.