METABOLISM OF CHLORAL HYDRATE IN MICE AND RATS AFTER SINGLE AND MULTIPLE DOSES

Chloral hydrate is a hepatocarcinogen in mice but not rats. To examine this species related difference, male and female B6C3F1 mice and Fisc her (F344) rats were treated by gavage with 1 or 12 doses of chloral h ydrate, and concentrations of the drug and its metabolites were determ ined in plasma at 0.25, 1, 3, 6, and 24 h and 2, 4, 8, and 16 d after the last treatment. Maximum levels of chloral hydrate were observed at the initial sampling time of 0.25 h. By 1 h, levels dropped substanti ally, and by 3 h, chloral hydrate could not be detected. Trichloroacet ic acid was the major metabolite found in the plasma, with peak levels being observed 1-6 h after dosing. The concentrations then slowly dec reased such that by 2 d this metabolite could no longer be detected. T richloroethanol was assayed as both the free alcohol and its glucuroni de. Maximum levels of trichoroethanol occurred at 0.25 h, and by 1-3 h approached the limits of detection. A pharmacokinetic model was const ructed to describe the metabolic data. The plasma half-life values of chloral hydrate were similar in bath species. In mice, the rate of eli mination of trichloroacetic acid was significantly increased after mul tiple doses; this difference was not observed with rats. The half-life of trichloroethanol and its glucuronide war; significantly greater in rats as compared to mice. None of the metabolic parameters appears to account for the hepatocarcinogenicity of chloral hydrate seen in mice but not rats.