RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP 242
OP 248
VO 21
IS 2
A1 K Kassahun
A1 T A Baillie
YR 1993
UL http://dmd.aspetjournals.org/content/21/2/242.abstract
AB 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)