Beland F A, Schmitt T C, Fullerton N F, Young J F
National Center for Toxicological Research, Jefferson, Arkansas 72079, USA.
J Toxicol Environ Health A. 1998 Jun 12;54(3):209-26. doi: 10.1080/009841098158917.
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.
水合氯醛对小鼠是一种肝癌致癌物，但对大鼠不是。为研究这种物种间差异，对雄性和雌性B6C3F1小鼠及Fischer（F344）大鼠经口灌胃给予1剂或12剂水合氯醛，并在末次给药后0.25、7、3、6和24小时以及2、4、8和16天测定血浆中该药物及其代谢物的浓度。在初始采样时间0.25小时观察到水合氯醛的最高水平。到1小时时，水平大幅下降，到3小时时，已检测不到水合氯醛。三氯乙酸是血浆中发现的主要代谢物，给药后1 - 6小时观察到峰值水平。然后浓度缓慢下降，到2天时该代谢物不再能被检测到。三氯乙醇以游离醇及其葡糖醛酸苷形式进行测定。三氯乙醇的最高水平出现在0.25小时，到1 - 3小时接近检测限。构建了一个药代动力学模型来描述代谢数据。水合氯醛的血浆半衰期值在两个物种中相似。在小鼠中，多次给药后三氯乙酸的消除速率显著增加；在大鼠中未观察到这种差异。与小鼠相比，大鼠中三氯乙醇及其葡糖醛酸苷的半衰期显著更长。似乎没有任何代谢参数能够解释在小鼠而非大鼠中观察到的水合氯醛的肝癌致癌性。
