MEMBRANE-TRANSPORT IN HEPATIC-CLEARANCE OF DRUGS .1. EXTENDED HEPATIC-CLEARANCE MODELS INCORPORATING CONCENTRATION-DEPENDENT TRANSPORT AND ELIMINATION PROCESSES

Purpose. The objective of the present study was to develop hepatic cle arance models which incorporate a unidirectional carrier-mediated upta ke and bidirectional diffusional transport processes for drug transpor t in the sinusoidal membrane of hepatocytes as well as nonlinear intri nsic elimination. Methods. Two models were derived which view the live r as two separate compartments, i.e., sinusoid and hepatocyte. Model I assumes the instantaneous complete mixing of drugs within each compar tment (similar to that of the ''well-stirred'' model), while model II assumes that the drug concentrations in both compartments decrease pro gressively in the direction of the hepatic blood flow path (similar to that of the ''parallel-tube'' model). Computer simulations were perfo rmed using a range of steady-state infusion rates for a substrate, whi le varying the V-max (capacity) and K-m (Michaelis-Menten constant) fo r the carrier-mediated uptake process, the diffusional clearance, the V-max and K-m for the intrinsic elimination process, blood flow and pr otein binding. Results. Simulations in which V-max and K-m for the sin usoidal membrane transporter and the diffusional clearance were varied , demonstrated that these membrane transport processes could affect th e clearance of drugs to a significant extent in both models. The estim ates for clearance of substrates with the same pharmacokinetic paramet ers are always lower in model I than in model II, although the quantit ative differences in parameter estimates between models varied, depend ing on the steady state infusion rates. Conclusions. These more genera l hepatic clearance models will be most useful for describing the hepa tic clearance of hydrophilic compounds, such as organic anions or cati ons, which exhibit facilitated uptake and limited membrane diffusion i n hepatocytes.