Fenobam [(Fn); N-(3-chlorophenyl)-N-(4,5-dihydro-l -methyl-4-0x0-1 Kimidazole-2-yl)urea] sulfate is a novel agent with potent anxiolytic activity in rats. [14C]Fn sulfate was administered as an oral solution (250 mglkg) 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 [l4C1Fn 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) Ndemethylation, a minor pathway for Fn in vivo.
Fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-l-methyl-4oxo-1H-imidazole-2-yl)urea is a novel agent with anxiolytic activity in rats.lS2 It has been shown to possess selective anxiolytic properties in animal models and in clinical trials, with a mode of action that differentiates it from the benzodiazepines.'-l0 Previous studies of fenobam disposition indicated that fenobam is rapidly and extensively metabolized by rats, dogs, and humans.4J1 The objective of this work was to identify in vitro and in vivo metabolites of fenobam in the rat to gain an understanding of the biotransformation pathways involved.