Nonlinear Pharmacokinetics of Ethanol Elimination in Long Sleep and Short Sleep Mice

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Abstract
Pharmacokinetic studies of ethanol elimination in humans and dogs have suggested that elimination from the blood can be best described through the application of MichaelikMenten enzyme kinetics. In an attempt to extend the application of the Michaelis-Menten model to ethanol elimination in mice, we measured elimination rates using serial blood samples obtained from the long sleep (Ls) and short sleep (SS) selected mouse lines following a bolus, intravenous ethanol infusion. A comparison was made between elimination rates as predicted by Widmark's linear model and by the nonlinear Michaelis-Menten model. Volume of distribution was also determined for each mouse line. Ethanol elimination in these mice conformed to the nonlinear model. Significantly greater Vmax and Km values were obtained for the SS mice than for the LS; however, no significant difference in linear elimination rates was found between lines. The LS mice exhibited a significantly greater volume of distribution than did the SS. The Michaelis-Menten model predicts that SS ethanol metabolism should be greater than LS metabolism at blood ethanol concentrations greater than 120 mg%. The results support the suggestion that ethanol elimination can be best described by Michaelis-Menten kinetics. Line differences in ethanol elimination may have resulted from changes in the doses used to select these mice and/or the induction of specific ethanol metabolizing systems.