Current models of hepatic pharmacokinetics: Flow effects on kinetic constants of ethanol elimination in perfused rat liver

Abstract

At present two different pharmacokinetic models of the enzymic elimination of substances from the blood flowing through the liver are used: the sinusoidal perfusion model assuming the elimination to take place at the local sinusoidal blood substrate concentration, falling continuously from the inlet to the outlet of the sinusoid, and the venous equilibration model assuming elimination at the hepatic outlet concentration. It is an ultimate requirement of such models that the estimates of the enzymic parameters V max and K m be independent of variations in hepatic blood flow rate. This was used to compare the two models experimentally. Ethanol was given at two successive constant infusion rates (7 and 10 μmol/min) to 11 livers from rats (200 g) perfused by a recirculating medium. In each of the infusion periods the hepatic blood flow rate was varied experimentally (10 and 17 ml/min, respectively). From the measured steady-state ethanol concentrations in the hepatic inlet and outlet, K m and V max were calculated from both models at both low and high blood flow rates. The K m calculated according to the venous equilibration model was significantly lower in the low-flow than in the high-flow periods (P < 0.05); this model is thus not consistent with data. V max values were not influenced by hepatic blood flow. The K m calculated according to the sinusoidal perfusion model were not influenced by flow (P < 0.5) and V max was also unchanged. The sinusoidal perfusion model is thus not inconsistent with data.