Pharmacodynamic responses of F344 rats to the mouse hepatocarcinogen oxazepam in a 90-day feed study

Oxazepam (Serax) is a widely used benzodiazepine anxiolytic agent and a metabolite of other benzodiazepines such as Valium and Librium. Chronic feeding studies indicated that oxazepam is an hepatocarcinogen in B6C3F1 mice but did not increase hepatic tumors in F344 rats. The present study was performed to compare the hepatic responses of rats with our previous findings in mice to explore the reason(s) for the dramatic differences in tumor response between the two species. Male F344 rats (10 per dose-time group) received diets containing oxazepam at 0, 25, 125, 2500, and 5000 ppm. Hepatocyte labeling indices were measured immuno-histochemically by PCNA and BrDU during the last 7 days before sacrifices after 15, 30, 45, and 90 days of dosing. Serum oxazepam was determined by reverse phase HPLC. Results indicated that oxazepam induced significant liver weight increases in a dose-related fashion by 15 days, which remained elevated for the entire study. No important clinical chemistry or pathology changes were noted except those related to hypertrophy. Cell proliferation was significantly increased in a dose-related manner by the 15-and 30-day timepoint in the 2500 and 5000 ppm groups. The most significant finding in the present study of oxazepam was plasma levels of the parent compound. Plasma levels in rats were dramatically lower than in B6C3F1 mice exposed to oxazepam in studies conducted earlier at the same dose levels. These results suggest that the early responses of rats and mice to oxazepam, such as cell proliferation and clinical chemistry parameters, are similar. Our previous studies demonstrated that oxazepam metabolites are excreted in the urine of rats, similar to humans, whereas mice excrete oxazepam metabolites in bile allowing enterohepatic recirculation, which results in high plasma levels of oxazepam. These data indicate that the rat excretes oxazepam kinetically (rate and route) similar to humans, but the mouse produces metabolites similar to humans.