Effects of unstirred Disse fluid, nonequilibrium binding, and surface-mediated dissociation on hepatic removal of albumin-bound organic anions

Proceeding from the observation that organic anions bound to albumin have hepatic extraction fractions that are unexpectedly high, we have studied a distributed model that accounts for this phenomenon by invoking sites on the cell surface that catalyze the dissociation of albumin-anion complexes. The present report extends this model to include nonequilibrium binding and rate-limiting diffusion of bound anion to the cell surface. Simulation analysis of the extended model provides an unambiguous basis for interpreting the apparent intrinsic clearance of free anion. The model is fully consistent with the transport data that we obtained with rose bengal [Am. J. Physiol. 248 (Gastrointest. Liver Physiol. 11): G702-G708, 1985] but is suited to estimating only selected components of the unknown parameter vector. Uncertainties inherent in an alternate approach are discussed and illustrated.