Hepatic Saturation Mechanism of Ethanol: Application of Mathematical Models to Ethanol Outflow Profiles in the Perfused Rat Liver

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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) × 0.4 (ml), 12 × 0.1, 24 × 0.1, and 3 × 0.1 mg (as a dose concentration × a volume) through the portal vein were analyzed by the statistical moment analysis and mathematical models (i.e., dispersion models). Results for 3 × 0.1 and 12 × 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 × 0.4 and 24 × 0.1 mg were larger than those for 3 × 0.1 and 12 × 0.1 mg doses and were similar. Kinetics after administration of 3 × 0.4 and 24 × 0.1 mg may be nonlinear. A difference in the relative dispersion (CV2) obtained by moment analysis between 3 × 0.4 and 24 × 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 × 0.4 and 24 × 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 × 0.4 and 24 × 0.1 mg (p < 0.05), whereas the elimination rate constant (ke) and the dispersion number values for these doses were similar. These findings demonstrated that there is difference in the no‐equilibrium process between 3 × 0.4 and 24 × 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.

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