Comparative metabolism and disposition of ethyl carbamate (urethane) in male fischer 344 rats and male B6C3F1 mice

Abstract

The metabolism, disposition, and excretion of ethyl carbamate (EC) was investigated following oral or iv administration of a wide range of doses to male rats and mice. At a low dose, 4.75 mg/kg, administered iv, approximately 98% was exhaled as CO 2 within 8 or 12 hr by mice or rats, respectively. However, as the dose increased, the percentage of dose eliminated as CO 2 decreased in a dose-dependent manner which was much more pronounced in rats than mice. At all doses studied, mice eliminated EC as CO 2 (as % dose) more rapidly than rats. Evidence of saturation of metabolism and elimination was observed at doses > 4.75 mg/kg in rats and >47.5 mg/kg in mice. Following iv administration of 47.5 or 475 mg/kg, EC was initially evenly distributed in all tissues of each species except fat. After the initial time point (15 min), rat tissues contained higher concentrations of 14C compared to tissues of mice receiving the same dose. The disappearance of 14C from blood and various tissues followed monoexponential kinetics with rates dependent upon the species and the dose but independent of the tissue. Following oral administration, EC was completely absorbed from the gastrointestinal tracts of rats and mice at all doses studied. Approximately 5, 0.7, and 1% of the doses were excreted in urine, in feces, and as volatile organics, respectively. EC was neither an inducer nor an inhibitor of its own metabolism to CO 2 following daily treatment of rats with oral doses of 47.5 mg/kg for 9 days. Only the parent compound was present in blood, lungs, skin, liver, kidney, muscle, and bile of treated rats. The urinary metabolic profile of EC was not affected by the route of administration in either species; however, in the rat but not in the mouse it was influenced by dose. Pretreatment of rats with piperonyl butoxide or SKF 525A (cytochrome P-450 inhibitors) or tri- o-cresyl phosphate (TOCP) or paraoxon (carboxylesterase inhibitors) or methyl carbamate (competitive substrate) did not greatly alter the metabolism of EC to CO 2. The in vitro metabolism of EC to CO 2 was not highly localized in any particular tissue or subcellular fraction of liver and was not affected by NADPH, GSH, NADH, or combinations of these cofactors. This work indicates that a number of studies of EC carcinogenicity have used doses that exceed the capacity of rats and mice to metabolize this chemical in a linear fashion.