The Hepatic Sinusoid is Not Well-Stirred: Estimation of the Degree of Axial Mixing by Analysis of Lobular Concentration Gradients Formed During Uptake of Thyroxine by the Perfused Rat Liver

Abstract

Two general models have been proposed for predicting the effects of metabolism, protein binding, and plasma flow on the removal of drugs by the liver. These models differ in the degree of plasma mixing assumed to exist within each hepatic sinusoid. The venous equilibrium model treats the sinusoid as a single well-stirred compartment, whereas the sinusoidal model effectively breaks up the sinusoid into a large number of sequentially perfused compartments which do not exchange their contents except through plasma flow. As a consequence, the sinusoidal model, but not the venous equilibrium model, predicts that the concentration of highly extracted drugs will decline as the plasma flows through the hepatic lobule. To determine which of these alternative models best describes the hepatic uptake process, we looked for evidence that concentration gradients are formed during the uptake of [125I]thyroxine by the perfused rat liver. Autoradiography of tissue slices after perfusion of the portal vein at physiologic flow rates with protein-free buffer containing [125I]thyroxine demonstrated a rapid exponential fall in grain density with distance from the portal venule, declining by half for each 8% of the mean length of the sinusoid. Reversing the direction of perfusate flow reversed the direction of the autoradiographic gradients, indicating that they primarily reflect differences in the concentration of thyroxine within the hepatic sinusoids rather than differences in the uptake capacity of portal and central hepatocytes. Analysis of the data using models in which each sinusoid was represented by different numbers of sequentially perfused compartments (1–20) indicated that at least eight compartments were necessary to account for the magnitude of the gradients seen. These results are incompatible with the venous equilibrium model, which predicts a uniform concentration at all points along the sinusoid, and suggest that it may be necessary to consider the effects of sinusoidal concentration gradients when studying the hepatic removal of efficiently extracted substances.