METABOLISM AND ELIMINATION OF OXAZEPAM IN F344 RATS

The antianxiety agent, oxazepam, is a mouse liver carcinogen as determined by a National Toxicology Program bioassay. An equivalent study in the F344 rat is currently in progress. In an effort to gain insight into whether the mouse or rat will be a better model for human risk assessment, extensive comparative metabolism studies have been conducted in both rodent species and compared with the human literature. In this study, male rats were treated with 25, 250, or 500 mg/kg of radiolabeled oxazepam. In addition, sex comparisons were made at 500 mg/kg after 0 and 14 days of 2500 ppm oxazepam in the feed to mimic bioassay conditions. Similar studies have already been conducted in mice. Recovery of administered activity was dose-dependent, with recovery approaching 100% at the low dose. In all groups, the order of importance of route of elimination was fecal > urinary > expired. No significant sex-dependent differences were detected. Oxidative metabolism and sulfate conjugation were the major routes of metabolism Pretreatment of animals with oxazepam-dosed feed resulted in evidence of hepatic enzyme induction. The rate of elimination for all three routes of elimination was elevated by dosed feed treatment, With regard to metabolite profile and routes of elimination, the rat is less like a human than the mouse.