caa a22 4500 47712576X CHVBK 20180405111649.0 cr unu---uuuuu 170330e19970601xx s 000 0 eng 10.1023/A:1012106623696 doi (NATIONALLICENCE)springer-10.1023/A:1012106623696 Membrane Transport in Hepatic Clearance of Drugs I: Extended Hepatic Clearance Models Incorporating Concentration-Dependent Transport and Elimination Processes [Elektronische Daten] [Younggil Kwon, Marilyn Morris] Purpose. The objective of the present study was to develop hepatic clearance models which incorporate a unidirectional carrier-mediated uptake and bidirectional diffusional transport processes for drug transport in the sinusoidal membrane of hepatocytes as well as nonlinear intrinsic elimination. Methods. Two models were derived which view the liver as two separate compartments, i.e., sinusoid and hepatocyte. Model I assumes the instantaneous complete mixing of drugs within each compartment (similar to that of the 'well-stirred' model), while model II assumes that the drug concentrations in both compartments decrease progressively in the direction of the hepatic blood flow path (similar to that of the 'parallel-tube' model). Computer simulations were performed using a range of steady-state infusion rates for a substrate, while varying theV max (capacity) and K m (Michaelis-Menten constant) for the carrier-mediated uptake process, the diffusional clearance, the V max and K m for the intrinsic elimination process, blood flow and protein binding. Results. Simulations in which V max and K m for the sinusoidal membrane transporter and the diffusional clearance were varied, demonstrated that these membrane transport processes could affect the clearance of drugs to a significant extent in both models. The estimates for clearance of substrates with the same pharmacokinetic parameters are always lower in model I than in model II, although the quantitative differences in parameter estimates between models varied, depending on the steady state infusion rates. Conclusions. These more general hepatic clearance models will be most useful for describing the hepatic clearance of hydrophilic compounds, such as organic anions or cations, which exhibit facilitated uptake and limited membrane diffusion in hepatocytes. Plenum Publishing Corporation, 1997 hepatic clearance nationallicence pharmacokinetic models nationallicence facilitated transport nationallicence diffusion nationallicence nonlinear intrinsic clearance nationallicence computer simulation 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), 774-779 0724-8741 14:6<774 1997 14 11095 https://doi.org/10.1023/A:1012106623696 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1023/A:1012106623696 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), 774-779 0724-8741 14:6<774 1997 14 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence SWISSBIB 47712576X BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer