Dose- and Route-Dependent Alteration of Metabolism and Toxicity of Chloroform in Fed and Fasting Rats

Abstract

Effects of overnight food deprivation on the metabolism and toxicity of chloroform (CHCl3) administered to rats per os (po), intraperitoneally (ip), or by inhalation (inh) at different doses were investigated. Rats that had been either deprived of food overnight or normally fed were challenged with CHCl3 either po (0, 100, 200, or 400 mg/kg), ip (0, 100, 200, or 400 mg/kg), or inh (0, 50, 100, or 500 ppm for 6 hr). Overnight fasting increased CHCl3 metabolism in vitro about threefold with a decrease of liver glutathione content to 67%. The fasting caused route- and dose-dependent alteration in the metabolism and toxicity of CHCl3. The area-under-the-curve (AUC) of blood CHCl3 concentration was invariably smaller following po than ip administration, and CHCl3 administered po caused more severe hepatic damage than did the same amount of CHCl3 administered ip. With po administration, the AUC (toxicity) of CHCl3 in fasting rats was significantly smaller (higher) than that of fed rats at a dose as small as 100 mg/kg, whereas, with ip administration at such a small dose, fasting caused no significant alteration in the AUC (toxicity). When rats were exposed by inhalation to CHCl3 vapor, food deprivation had little or no effect on either the blood concentration or the toxicity until the exposure concentration was raised to 500 ppm. The present study indicates that po administration is different from both ip and inh administration with regard to the effect of enzyme induction on the toxicokinetics of CHCl3, mainly due to the first-pass metabolism unique to po administration.