On the design and interpretation of experiments to elucidate albumin-dependent hepatic uptake.

The liver's apparently anomalous extraction of organic anions tightly bound to albumin continues to provoke controversy and confusion. Decisive experiments have proved difficult to design, and mathematical models have usually been constructed to defend one or another putative mechanism to the exclusion of others. To stimulate more decisive experiments and as an aid to interpreting those already reported, we discuss a general formulation of the problem that predicts the clearance pattern to be expected when facilitated dissociation and codiffusion are joint determinants of the uptake flux. The results provide an approach to modeling the various mechanisms by which the concentration of bound ligand at the cell surface could be a driving force for uptake. Further we present new calculations to clarify the interpretation of net ligand clearance when the removal of free ligand is the result of bidirectional fluxes into and out of an unstirred sink. Applied to a previously published comparison of the uptake performances of hepatocytes and polyethylene, the new calculations support the inference that facilitated dissociation of albumin-palmitate complexes occurs at or near the hepatocyte surface.