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OtherNEUROPHARMACOLOGY

Time Course of α-Fluorinated Valproic Acid in Mouse Brain and Serum and its Effect on Synaptosomal γ-Aminobutyric Acid Levels in Comparison to Valproic Acid

Wei Tang, Jan Palaty and Frank S. Abbott
Journal of Pharmacology and Experimental Therapeutics September 1997, 282 (3) 1163-1172;
Wei Tang
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Jan Palaty
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Frank S. Abbott
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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 (pKa = 3.55) than VPA (pKa = 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.

Footnotes

  • Send reprint requests to: Dr. Frank S. Abbott, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, B.C., Canada, V6T 1Z3.

  • ↵1 This work was supported by a program grant from the Medical Research Council of Canada. A preliminary account of these studies was presented at the 42nd ASMS conference of mass spectrometry and allied topics, May 29 to June 3, Chicago, IL, 1994.

  • ↵2 Current address: Department of Drug Metabolism, Merck & Co., PO Box 2000, RY80L-109, Rahway, NJ 07065-0900.

  • Abbreviations:
    CoA
    co-enzyme A
    CSF
    cerebrospinal fluid
    GABA
    γ-aminobutyric acid
    PTZ
    1,5-pentamethylenetetrazole
    VPA
    valproic acid, 2-propylpentanoic acid
    (E)-2
    4-diene VPA, (E)-2-propyl-2,4-pentadienoic acid
    4-ene VPA
    2-propyl-4-pentenoic acid
    (E)-2-ene VPA
    (E)-2-propyl-2-pentenoic acid
    α-fluoro VPA
    2-fluoro-2-propylpentanoic acid
    α-fluoro VPA-Gln
    N 2-(2-fluoro-2-propylpentanoyl)glutamine
    3-keto-4-ene VPA
    2-propyl-3-oxo-4-pentenoic acid
    tBDMS
    tert-butyldimethylsilyl
    TMS
    trimethylsilyl
    TFA
    trifluoroacetic acid
    HPLC
    high-performance liquid chromatography
    • Received October 7, 1996.
    • Accepted May 27, 1997.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 282, Issue 3
1 Sep 1997
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OtherNEUROPHARMACOLOGY

Time Course of α-Fluorinated Valproic Acid in Mouse Brain and Serum and its Effect on Synaptosomal γ-Aminobutyric Acid Levels in Comparison to Valproic Acid

Wei Tang, Jan Palaty and Frank S. Abbott
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1163-1172;

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OtherNEUROPHARMACOLOGY

Time Course of α-Fluorinated Valproic Acid in Mouse Brain and Serum and its Effect on Synaptosomal γ-Aminobutyric Acid Levels in Comparison to Valproic Acid

Wei Tang, Jan Palaty and Frank S. Abbott
Journal of Pharmacology and Experimental Therapeutics September 1, 1997, 282 (3) 1163-1172;
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