Membrane transport in hepatic clearance of drugs. I: Extended hepatic clearance models incorporating concentration-dependent transport and elimination processes.
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 the Vmax (capacity) and Km (Michaelis-Menten constant) for the carrier-mediated uptake process, the diffusional clearance, the Vmax and Km for the intrinsic elimination process, blood flow and protein binding. RESULTS: Simulations in which Vmax and Km 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.