title: 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.
abstract: 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)
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
authors.forename: K
authors.initials: K
authors.lastname: Kassahun
authors.forename: T A
authors.initials: TA
authors.lastname: Baillie
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D066298:In Vitro Techniques; D007527:Isoenzymes; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology* / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014635:Valproic Acid / Q000378:metabolism*
chemical_list: D000927:Anticonvulsants; D005229:Fatty Acids, Monounsaturated; D007527:Isoenzymes; D009249:NADP; C014168:2-propyl-2-pentenoic acid; D014635:Valproic Acid; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital