AXIAL TISSUE DIFFUSION CAN ACCOUNT FOR THE DISPARITY BETWEEN CURRENT MODELS OF HEPATIC ELIMINATION FOR LIPOPHILIC DRUGS

An assumption of previous models of hepatic elimination is that there is negligible axial diffusion in the liver. We show, by construction o f a stochastic model and analysis of published data, that compounds wh ich are readily diffusible and partitioned into hepatocytes may underg o axial tissue diffusion. The compounds most likely to be affected by axial tissue diffusion are the lipophilic drugs for which the cell mem branes provide little resistance and which are highly extracted, there by creating steep concentration gradients along the sinusoid at steady state. This phenomenon greatly modifies the availability of the compo und under conditions of altered hepatic blood flow and protein binding . For moderately diffusible compounds, these relationships are similar to those predicted by the simplistic venous-equilibrium model. Hence, the paradoxical ability of the venous-equilibrium model to describe t he steady-state kinetics of lipophilic drugs such as lidocaine, meperi dine, and propranolol may be finally resolved. The effects of axial ti ssue diffusion and vascular dispersion on hepatic availability of drug s are compared. Vascular dispersion is of major importance to the avai lability of poorly diffusible compounds, whereas axial tissue diffusio n becomes increasingly dominant for highly diffusive and partitioned s ubstances.