caa a22 4500 477125891 CHVBK 20180405111649.0 cr unu---uuuuu 170330e19970601xx s 000 0 eng 10.1023/A:1012158607766 doi (NATIONALLICENCE)springer-10.1023/A:1012158607766 Membrane Transport in Hepatic Clearance of Drugs II: Zonal Distribution Patterns of Concentration-Dependent Transport and Elimination Processes [Elektronische Daten] [Younggil Kwon, Marilyn Morris] 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. Plenum Publishing Corporation, 1997 pharmacokinetic models nationallicence nonlinear transport nationallicence nonlinear intrinsic elimination nationallicence zonal distribution nationallicence blood and tissue concentration gradient profiles nationallicence Kwon Younggil Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, 14260, Amherst, New York aut Morris Marilyn Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, 14260, Amherst, New York aut Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/6(1997-06-01), 780-785 0724-8741 14:6<780 1997 14 11095 https://doi.org/10.1023/A:1012158607766 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012158607766 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Kwon Younggil Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, 14260, Amherst, New York aut NATIONALLICENCE 700 1- Morris Marilyn Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, 14260, Amherst, New York aut NATIONALLICENCE 773 0- Pharmaceutical Research Kluwer Academic Publishers-Plenum Publishers 14/6(1997-06-01), 780-785 0724-8741 14:6<780 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence SWISSBIB 47712576X BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer