Journal of Pharmaceutical Sciences 1995-02-01

In vitro and in vivo metabolism of the antianxiolytic agent fenobam in the rat.

W N Wu, L A McKown, P J O'Neill

Index: J. Pharm. Sci. 84(2) , 185-9, (1995)

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Abstract

Fenobam [(Fn); N-(3-chlorophenyl)-N-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl)urea] sulfate is a novel agent with potent anxiolytic activity in rats. [14C]Fn sulfate was administered as an oral solution (250 mg/kg) to male Wistar rats, and 52% of the administered dose was excreted in urine (0-5 days). In vitro metabolism of Fn was studied by incubating [14C]Fn with rat hepatic 9000 x g supernatant preparations. Unchanged Fn and a total of six metabolites were isolated, quantified, and identified from the urine and liver 9000 x g supernatant samples by column chromatography; TLC; UV, IR, and NMR spectroscopy; MS; and comparison with synthetic samples. Four metabolic pathways for Fn are proposed: (1) hydroxylation at the phenyl ring to form 4-hydroxyphenyl-Fn, a major pathway in vivo (12% of the sample radioactivity) but a minor pathway in vitro (4% of the sample radioactivity); (2) hydroxylation at the creatinine ring to form 5-hydroxy-Fn (19%) of the sample radioactivity), a dominant pathway in vitro but not in vivo; (3) oxidative cleavage at the creatinine ring (loss of a ketene unit), a minor pathway for Fn but an important pathway for 4-hydroxyphenyl-Fn in vivo; and (4) N-demethylation, a minor pathway for Fn in vivo.