METABOLISM AND ELIMINATION OF OXAZEPAM IN B6C3F1 AND SWISS-WEBSTER MICE

The National Toxicology Program has recently determined oxazepam to be hepatocarcinogenic in mice. To aid in the assessment of the risks ass ociated with human use of this drug, the metabolism and elimination of oxazepam in mice were exhaustively examined in B6C3F1 and Swiss-Webst er mice. In this study males were given 25, 250, and 500 mg/kg by gava ge, a range that includes doses found to be carcinogenic and noncarcin ogenic in the National Toxicology Program bioassay. Metabolism of oxaz epam by female mice of both strains was studied following administrati on of 500 mg/kg. More than 90% of the recovered activity was identifie d. Few strain differences were detected. Females of both strains metab olize oxazepam to a slightly greater extent than do males. Dose-depend ent differences were detected, but they were usually nonlinear over th e range examined. The routes of elimination in mice given a single dos e of oxazepam were by order of importance: fecal > urinary > expired a ir. Pretreatment with dosed feed for 14 days (to model autoinduction i n bioassay animals) resulted in a significant shift from the fecal to the urinary route of elimination, an approximately 2-fold increase in elimination of oxazepam glucuronide, and a significant decrease in exc retion of unchanged oxazepam. Results of this study indicate that foll owing constant exposure to oxazepam, mice metabolize and eliminate oxa zepam in a manner more similar to that by humans than that by naive mi ce. This observation enhances the significance of data obtained in the bioassay and the extrapolation of that data to predict risks to human health.