TY - JOUR T1 - Cytochrome P-450-mediated dehydrogenation of 2-n-propyl-2(E)-pentenoic acid, a pharmacologically-active metabolite of valproic acid, in rat liver microsomal preparations. JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 242 LP - 248 VL - 21 IS - 2 AU - K Kassahun AU - T A Baillie Y1 - 1993/03/01 UR - http://dmd.aspetjournals.org/content/21/2/242.abstract N2 - The pharmacologically active metabolite of valproic acid (VPA), (E)-delta 2-VPA, is being investigated for therapeutic use as a potentially nonteratogenic antiepileptic drug. Although its anticonvulsant properties have been studied extensively, there is little information on the metabolic fate of (E)-delta 2-VPA in mammalian systems. In this in vitro study, we investigated the biotransformation of (E)-delta 2-VPA in rat liver microsomal preparations. Acidified microsomal incubation products were extracted with ethyl acetate, converted to trimethylsilyl or pentafluorobenzyl derivatives, and analyzed by GC/MS. From the resulting electron impact and negative ion chemical ionization spectra, an oxygenated species and a diene compound were found to be the major microsomal metabolites of (E)-delta 2-VPA. These metabolites, whose formation was shown to be cytochrome P-450-dependent, were identified as 4-OH-(E)-delta 2-VPA and (E)-delta 2,4-VPA by comparing their GC/MS properties with those of synthetic reference materials. Quantification of the metabolites by selected ion monitoring GC/electron impact-MS showed that formation of the diene paralleled that of the allylic alcohol as a function of time, when the ratio of the diene to the allylic alcohol remained constant at 0.45 +/- 0.045 during the 60-min incubation. This value for partition ratio indicates that the formation of the diene was a relatively favored metabolic pathway compared with the cytochrome P-450-catalyzed dehydrogenation of VPA to give delta 4-VPA.(ABSTRACT TRUNCATED AT 250 WORDS) ER -