DOSE-DEPENDENT AND ROUTE-DEPENDENT ALTERATION OF METABOLISM AND TOXICITY OF CHLOROFORM IN FED AND FASTING RATS

Effects of overnight food deprivation on the metabolism and toxicity o f chloroform (CHCl3) administered to rats per os (po), intraperitoneal ly (ip), or by inhalation (inh) at different doses were investigated, Rats that had been either deprived of food overnight or normally fed w ere 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), O vernight fasting increased CHCl3 metabolism in vitro about threefold w ith a decrease of liver glutathione content to 67%, The fasting caused route- and dose-dependent alteration in the metabolism and toxicity o f CHCl3. The area-under-the-curve (AUG) of blood CHCl3 concentration w as invariably smaller following po than ip administration, and CHCl3 a dministered po caused more severe hepatic damage than did the same amo unt of CHCl3 administered ip. With po administration, the AUC (toxicit y) of CHCl3 in fasting rats was significantly smaller (higher) than th at of fed rats at a dose as small as 100 mg/kg, whereas, with ip admin istration at such a small dose, fasting caused no significant alterati on in the AUC (toxicity). When rats were exposed by inhalation to CHCl 3 vapor, food deprivation had little or no effect on either the blood concentration or the toxicity until the exposure concentration was rai sed to 500 ppm. The present study indicates that po administration is different from both ip and inh administration with regard to the effec t of enzyme induction on the toxicokinetics of CHCl3, mainly due to th e first-pass metabolism unique to po administration. (C) 1995 Academic Press, Inc.