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 Fischer (F344) rats were treated by gavage with 1 or 12 doses of chloral hydrate, and concentrations of the drug and its metabolites were determined in plasma at 0.25, 7, 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 substantially, and by 3 h, chloral hydrate could not be detected. Trichloroacetic acid was the major metabolite found in the plasma, with peak levels being observed 1-6 h after dosing. The concentrations then slowly decreased such that by 2 d this metabolite could no longer be detected. Trichloroethanol was assayed as both the free alcohol and its glucuronide. Maximum levels of trichoroethanol occurred at 0.25 h, and by 1-3 h approached the limits of detection. A pharmacokinetic model was constructed to describe the metabolic data. The plasma half-life values of chloral hydrate were similar in both species. In mice, the rate of elimination of trichloroacetic acid was significantly increased after multiple doses; this difference was not observed with rats. The half-life of trichloroethanol and its glucuronide was 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.