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 associated with human use of this drug, the metabolism and elimination of oxazepam in mice were exhaustively examined in B6C3F1 and Swiss-Webster mice. In this study males were given 25, 250, and 500 mg/kg by gavage, a range that includes doses found to be carcinogenic and noncarcinogenic in the National Toxicology Program bioassay. Metabolism of oxazepam by female mice of both strains was studied following administration of 500 mg/kg. More than 90% of the recovered activity was identified. Few strain differences were detected. Females of both strains metabolize oxazepam to a slightly greater extent than do males. Dose-dependent differences were detected, but they were usually nonlinear over the range examined. The routes of elimination in mice given a single dose of oxazepam were by order of importance: fecal > urinary > expired air. Pretreatment with dosed feed for 14 days (to model autoinduction in 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 excretion of unchanged oxazepam. Results of this study indicate that following constant exposure to oxazepam, mice metabolize and eliminate oxazepam in a manner more similar to that by humans than that by naive mice. This observation enhances the significance of data obtained in the bioassay and the extrapolation of that data to predict risks to human health.