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

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 Vmax and Km 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 mumol/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, Km and Vmax were calculated from both models at both low and high blood flow rates. The Km calculated according to the venous equilibration model was significantly lower in the low-flow than in the high-flow periods (P less than 0.05); this model is thus not consistent with data. Vmax values were not influenced by hepatic blood flow. The Km calculated according to the sinusoidal perfusion model were not influenced by flow (P less than 0.5) and Vmax was also unchanged. The sinusoidal perfusion model is thus not inconsistent with data.