Membrane Transport in Hepatic Clearance of Drugs II: Zonal Distribution Patterns of Concentration-Dependent Transport and Elimination Processes

Purpose. The objective of the present simulation study was to investigate the effects of hepatic zonal heterogeneity of membrane transporter proteins and intrinsic elimination activities on hepatic clearance (CL) and drug concentration gradient profiles in the sinusoidal blood and hepatocytes.Methods. The model used in the simulations assumes an apparent unidirectional carrier-mediated transport and a bidirectional diffusion of substrates in the hepatic sinusoidal membrane as well as a nonlinear intrinsic elimination. Three different distribution patterns of the transporter and the metabolizing enzyme along the sinusoidal flow path were used for the simulations. The effects of changes in the Michaelis-Menten parameters for those nonlinear processes, and in the unbound fractions of the drug in blood and tissue components were investigated.Results. Significant differences in CL occurred when the distribution patterns of the transporter and/or the metabolizing enzyme activities were altered under nonlinear conditions. The highest CL values were observed when the transporter and the metabolizing enzyme had similar distribution patterns within the liver acinus, while opposite distribution patterns produced the lowest CL values. Tissue concentration profiles were significantly affected by the distribution patterns of the transporter, but the changes in blood concentration profiles were relatively small. Altering protein binding in blood produced significant changes in CL, and blood and tissue concentration gradients, while altering protein binding in tissue affected only drug accumulation patterns within hepatocytes, regardless of the distribution patterns of the transporter or the metabolizing enzyme.Conclusions. The present simulations demonstrate that hepatic zonal heterogeneities in the transporter and the metabolizing enzyme activities can significantly influence hepatic clearance and/or drug concentration gradient profiles in the sinusoidal blood and hepatocytes.