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Zhang K, Lepage F, Cuvier G, et al. The metabolic fate of stiripentol in the rat. Studies on cytochrome P-450-mediated methylenedioxy ring cleavage and side chain isomerism. Drug Metab Dispos. 1990;18(5):794-803
Zhang, K., Lepage, F., Cuvier, G., Astoin, J., Rashed, M. S., & Baillie, T. A. (1990). The metabolic fate of stiripentol in the rat. Studies on cytochrome P-450-mediated methylenedioxy ring cleavage and side chain isomerism. Drug metabolism and disposition: the biological fate of chemicals, 18(5), 794-803.
Zhang, K, et al. "The metabolic fate of stiripentol in the rat. Studies on cytochrome P-450-mediated methylenedioxy ring cleavage and side chain isomerism." Drug metabolism and disposition: the biological fate of chemicals vol. 18,5 (1990): 794-803.
Zhang K, Lepage F, Cuvier G, Astoin J, Rashed MS, Baillie TA. The metabolic fate of stiripentol in the rat. Studies on cytochrome P-450-mediated methylenedioxy ring cleavage and side chain isomerism. Drug Metab Dispos. 1990 Sep-Oct;18(5):794-803. PMID: 25989628.
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Drug Metab Dispos. 1990 Sep-Oct;18(5):794-803.

The metabolic fate of stiripentol in the rat. Studies on cytochrome P-450-mediated methylenedioxy ring cleavage and side chain isomerism.

Drug metabolism and disposition: the biological fate of chemicals

K Zhang, F Lepage, G Cuvier, J Astoin, M S Rashed, T A Baillie

Affiliations

  1. Department of Medicinal Chemistry, University of Washington, USA.

PMID: 25989628

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.

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