TY - JOUR T1 - Effect of α-Fluorination of Valproic Acid on Valproyl-<em>S</em>-Acyl-CoA Formation in Vivo in Rats JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1210 LP - 1215 VL - 29 IS - 9 AU - Mark P. Grillo AU - Grazia Chiellini AU - Marco Tonelli AU - Leslie Z. Benet Y1 - 2001/09/01 UR - http://dmd.aspetjournals.org/content/29/9/1210.abstract N2 - Studies designed to compare valproic acid (VPA) with its α-fluorinated derivative (F-VPA) for their abilities to form acyl-CoA thioester derivatives in vivo are described. Recent studies have shown that α-fluorination of a hepatotoxic metabolite of VPA (Δ4-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 α-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 α-fluoro substitution, we propose that metabolism of VPA by acyl-CoA formation may mediate the hepatotoxicity of the drug. The American Society for Pharmacology and Experimental Therapeutics ER -