Modeling thyroxine transport to liver: rejection of the "enhanced dissociation" hypothesis as applied to thyroxine

Three models for the hepatic uptake of thyoxine (T4) from human plasma were considered: 1) uptake occurs exclusively via the pool of free T4 after spontaneous dissociation of T4-plasma-protein complexes, 2) uptake occurs primarily via the pool of bound T4 by the interaction of one or more binding proteins with the cell-surface membrane, and 3) uptake occurs primarily by "enhanced dissociation" of T4 from one or more of its binding proteins within the sinusoids. Each of these models was examined in relation to well-accepted unidirectional uptake and steady-state kinetics data that indicate that 1) between 4 and 24% of the T4 in normal human serum is taken up unidirectionally by the liver in a single pass, and 2) the in vivo disposal rate of T4 is unaffected by primary changes in the plasma concentration of thyroid hormone-binding globulin. Both analytical and numerical techniques were used. The first two models were found to be compatible with both the steady-state kinetics data and the unidirectional uptake data, given certain assumptions in each of the models. Although theoretically distinguishable on the basis of unidirectional uptake data, uncertainty over the true uptake (influx) rate constant for free T4 prevented resolution between these two models. In contrast, the third model, that of enhanced dissociation [W. M. Pardridge, Am. J. Physiol. 252 (Endocrinol. Metab. 15): E157-E164, 1987], was found, as currently formulated with respect to T4, to be incompatible with both the steady-state kinetics data and the unidirectional uptake data.(ABSTRACT TRUNCATED AT 250 WORDS)