Hepatic saturation mechanism of ethanol: application of mathematical models to ethanol outflow profiles in the perfused rat liver.
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.
Matsumoto
H
H
Department of Legal Medicine, Kyoto University Faculty of Medicine, Japan.
Fukui
Y
Y
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
D000431:Ethanol