title: The metabolic fate of stiripentol in the rat. Studies on cytochrome P-450-mediated methylenedioxy ring cleavage and side chain isomerism.
abstract: Following a single oral dose (200 mg Kg (-1) of stiripentol t (1) o adult male Sprague-Dawley rats, a total of 15 metabolites (accounting collectively for 44% of the administered dose collected over 48 hr) were identified in urine by GC/MS techniques, while only unchanged I (accounting for a further 12.8% and 23.5% of the dose in two rats) was present in extracts of feces. The major pathway of metabolism I involved cytochrome P-450-mediated cleavage of the methylenedioxy ring to yield catechol derivatives. In vitro studies employing rat hepatic microsomal preparations showed that this reaction was associated with the formation of a type III optical difference spectrum, indicative of the generation of an inhibitory ligand-complex between a reactive metabolite of I and the prosthetic heme moiety of cytochrome P-450. Mechanistic studies on the origin of a series of metabolites of I in which the allylic alcohol side chain had been replaced by an isomeric 3-pentanone structure pointed to the operation of a two-step sequence involving initial alcohol oxidation followed by olefin reduction. The former reaction appeared to be catalyzed in part by cytochrome P-450 enzymes. It is concluded that the rat represents an appropriate model for humans in the conduct of detailed studies of the metabolic fate of I and analogs thereof.
authors.affiliation: Department of Medicinal Chemistry, University of Washington, USA.
authors.forename: K
authors.initials: K
authors.lastname: Zhang
authors.forename: F
authors.initials: F
authors.lastname: Lepage
authors.forename: G
authors.initials: G
authors.lastname: Cuvier
authors.forename: J
authors.initials: J
authors.lastname: Astoin
authors.forename: M S
authors.initials: MS
authors.lastname: Rashed
authors.forename: T A
authors.initials: TA
authors.lastname: Baillie