Influence of plasma protein binding kinetics on hepatic clearance assessed from a “tube” model and a “well-stirred” model

Abstract

The potential influence of protein binding kinetics on elimination from liver sinusoids was evaluated by means of a “well-stirred” model (I) and a “tube” model (II). When the dissociation rate constant (k₋₁) is at the estimated maximum, equilibrium is maintained during the passage of drug through the eliminating organ, and hence dissociation as such has no limiting effect on elimination. When, however, k₋₁ is at the estimated minimum, equilibrium is not maintained, the unbound fraction is reduced during the passage, and a significant decrease in the extraction ratio occurs when the unbound fraction is 0.01 or less. The models were furthermore used to investigate the effect of saturation, of both the binding protein and the elimination process, on elimination.