title: Hepatic saturation mechanism of ethanol: application of mathematical models to ethanol outflow profiles in the perfused rat liver.
abstract: The saturation mechanism of hepatic ethanol (EtOH) elimination was studied in the perfused rat liver. EtOH outflow profiles after the instantaneous administration of 3 (mg/ml) x 0.4(ml), 12 x 0.1, 24 x 0.1, and 3 x 0.1 mg (as a dose concentration x a volume) through the portal vein were analyzed by the statistical moment analysis and mathematical models (i.e., dispersion models). Results for 3 x 0.1 and 12 x 0.1 mg doses by moment analysis were similar. This demonstrated that the elimination exhibits linear kinetics. Recovery ratio and hepatic volume of distribution for 3 x 0.4 and 24 x 0.1 mg were larger than those for 3 x 0.1 and 12 x 0.1 mg doses and were similar. Kinetics after administration of 3 x 0.4 and 24 x 0.1 mg may be nonlinear. A difference in the relative dispersion (CV2) obtained by moment analysis between 3 x 0.4 and 24 x 0.1 mg doses indicated different properties of the nonlinear elimination kinetics. There were no differences in all the parameters in the one-compartment dispersion model between 3 x 0.4 and 24 x 0.1 mg doses. In the two-compartment dispersion model, there were differences in the blood volume (VB) and the forward partition rate constant (k12) between 3 x 0.4 and 24 x 0.1 mg (p < 0.05), whereas the elimination rate constant (k sigma) and the dispersion number values for these doses were similar. These findings demonstrated that there is difference in the no-equilibrium process between 3 x 0.4 and 24 x 0.1 mg doses. Therefore, we suggest that the continuous EtOH input into the liver causes the saturation of enzyme pathways and the change of the nonequilibrium process.
authors.affiliation: Department of Legal Medicine, Kyoto University Faculty of Medicine, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Matsumoto
authors.forename: Y
authors.initials: Y
authors.lastname: Fukui
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000493:pharmacokinetics*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D008962:Models, Theoretical; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000431:Ethanol