MEMBRANE-TRANSPORT IN HEPATIC-CLEARANCE OF DRUGS .2. ZONAL DISTRIBUTION PATTERNS OF CONCENTRATION-DEPENDENT TRANSPORT AND ELIMINATION PROCESSES

Purpose. The objective of the present simulation study was to investig ate the effects of hepatic zonal heterogeneity of membrane transporter proteins and intrinsic elimination activities on hepatic clearance (C L) and drug concentration gradient profiles in the sinusoidal blood an d hepatocytes. Methods. The model used in the simulations assumes an a pparent 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 patter ns of the transporter and the metabolizing enzyme along the sinusoidal flow path were used for the simulations. The effects of changes in th e Michaelis-Menten parameters for those nonlinear processes, and in th e unbound fractions of the drug in blood and tissue components were in vestigated. Results. Significant differences in CL occurred when the d istribution patterns of the transporter and/or the metabolizing enzyme activities were altered under nonlinear conditions. The highest CL va lues were observed when the transporter and the metabolizing enzyme ha d similar distribution patterns within the liver acinus, while opposit e distribution patterns produced the lowest CL values. Tissue concentr ation profiles were significantly affected by the distribution pattern s of the transporter, but the changes in blood concentration profiles were relatively small. Altering protein binding in blood produced sign ificant changes in CL, and blood and tissue concentration gradients, w hile altering protein binding in tissue affected only drug accumulatio n patterns within hepatocytes, regardless of the distribution patterns of the transporter or the metabolizing enzyme. Conclusions. The prese nt simulations demonstrate that hepatic zonal heterogeneities in the t ransporter and the metabolizing enzyme activities can significantly in fluence hepatic clearance and/or drug concentration gradient profiles in the sinusoidal blood and hepatocytes.