The kinetics of urethane elimination in the mouse

Data from several investigators suggest that the prevalence of urethane-induced lung adenomas in the mouse is more nearly linearly related to the square of the urethane dose than to the dose itself. However, the relationship between urethane dose and integrated internal exposure to urethane has not been established. Outbred male Swiss mice between 41 and 45 days old were injected ip with one of seven doses of urethane ranging from 0.4 to 1.8 mg/g. The rate of elimination of urethane from the blood was followed by assaying the ethanol liberated from urethane by alkaline hydrolysis. The results indicated that urethane elimination is saturable, and saturated at all doses used, with a Vmax of 0.087 mg/ml/hr. Thus, internal exposure to urethane, measured as the area under the blood concentration, time curve, is not linearly related to urethane dose. In the range of doses used in this study, the area under the curve is C0(2)/2Vmax or (D/VD)2 (1/2Vmax), where C0 is the initial concentration; D, the dose; and VD, the volume of distribution. This relationship can be used to predict internal exposure to urethane as a function of dose.