title: Effect of alpha-fluorination of valproic acid on valproyl-S-acyl-CoA formation in vivo in rats.
abstract: Studies designed to compare valproic acid (VPA) with its alpha-fluorinated derivative (F-VPA) for their abilities to form acyl-CoA thioester derivatives in vivo are described. Recent studies have shown that alpha-fluorination of a hepatotoxic metabolite of VPA (Delta(4)-VPA) resulted in a nonhepatotoxic derivative. We hypothesize that the decrease in hepatotoxicity may be related to a lack of formation of the intermediary acyl-CoA thioester. To determine the effect of alpha-fluoro substitution on acyl-CoA formation, we synthesized F-VPA and compared it with VPA for its ability to form the acyl-CoA thioester derivative in vivo in rat liver. Thus, after dosing rats with VPA or F-VPA, animals were sacrificed (0.05-, 0.5-, 1-, 2-, and 5-h postadministration) for the analysis of liver tissue. High-performance liquid chromatography (HPLC) and electrospray ionization/tandem mass spectrometry analysis of liver extracts from VPA-dosed rats showed the presence of VPA-CoA that was maximal after 0.5 h (185 nmol/g of liver) and was still measurable 5-h postadministration (90 nmol/g of liver). In agreement with our hypothesis, F-VPA did not form the corresponding acyl-CoA derivative as determined by the absence of F-VPA-CoA upon HPLC analysis of liver extracts from F-VPA-dosed rats. Further examination of liver tissue for the presence of free acids revealed that the differences in acyl-CoA formation cannot be explained by differences in VPA and F-VPA free acid concentrations. From these observations and related studies showing the lack of toxicity due to alpha-fluoro substitution, we propose that metabolism of VPA by acyl-CoA formation may mediate the hepatotoxicity of the drug.
authors.affiliation: Department of Biopharmaceutical Sciences, University of California-San Francisco, 513 Parnassus Ave., San Francisco, CA 94143-0446, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Grillo
authors.forename: G
authors.initials: G
authors.lastname: Chiellini
authors.forename: M
authors.initials: M
authors.lastname: Tonelli
authors.forename: L Z
authors.initials: LZ
authors.lastname: Benet
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism*; D000818:Animals; D005461:Fluorine; D008401:Gas Chromatography-Mass Spectrometry; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014635:Valproic Acid / Q000032:analysis / Q000378:metabolism* / Q000633:toxicity*
chemical_list: D000214:Acyl Coenzyme A; D005461:Fluorine; D014635:Valproic Acid