Discrimination between the venous equilibrium and sinusoidal models of hepatic drug elimination in the isolated perfused rat liver by perturbation of propranolol protein binding.

To discriminate between two widely used models of hepatic drug elimination, the venous equilibrium and sinusoidal models, we examined the effect of altering perfusate protein binding on the hepatic elimination of the highly cleared drug, propranolol, by the isolated perfused rat liver. We investigated specifically the relationship between the unbound fraction of drug perfusing the liver and the steady-state unbound drug concentration in hepatic venous effluent (i.e., in the perfusate reservoir) after a constant infusion of drug (1.37 mg/hr) into the portal vein. Each rat liver (n = 21) was perfused over 60 min at one of seven different protein concentrations, such that the unbound fraction of propranolol in the portal venous perfusate was varied from 0.1 to 0.65. The unbound steady-state propranolol concentration in the hepatic venous effluent remained unchanged, despite an almost 7-fold increase in the free fraction of propranolol perfusing the liver. The data conform precisely to the predictions of the venous equilibrium model and are incompatible with the sinusoidal model, which predicts a 100-fold decrease in unbound reservoir concentration. This study therefore establishes that the apparently "unphysiological" venous equilibrium model represents a valid description of the hepatic elimination of this high clearance compound.