HEPATIC ICG REMOVAL IN THE PIG DEPENDS ON PLASMA-PROTEIN AND HEMATOCRIT - EVIDENCE OF SINUSOIDAL BINDING DISEQUILIBRIUM AND UNSTIRRED WATERLAYER EFFECTS

The influence of binding protein concentration and hematocrit on hepat ic uptake of indocyanine green (ICG) was studied in anesthetized pigs during constant infusion of ICG. By exchange transfusions, we either s ubstituted plasma protein with dextran 70 (n = 8) or changed hematocri t (n = 8), Intrinsic hepatic clearance of ICG, K, was calculated from plasma flow rate and concentrations in peripheral artery and liver vei n after correction for extrahepatic distribution. By analyzing the rel ative change of K versus either the protein dilution factor or the cha nge in plasma volume fraction (1-hct), we evaluated four current model s for hepatic uptake of protein-bound substances even though a number of model parameters were unknown (parameter-free testing), Protein dil ution factors (unitless) of 0.506 +/- 0.027, 0.673 +/- 0.011, and 0.74 9 +/- 0.028 were associated with inverse K ratios of 0.621 +/- 0.025, 0.758 +/- 0.021, and 0.817 +/- 0.013, These data rejected the traditio nal hypothesis that ICG uptake is proportional to the unbound concentr ation, They were compatible with development of binding disequilibrium along the sinusoidal lumen, an unstirred water layer close to the hep atocyte surface, or facilitated uptake from the bound pool, A plasma v olume ratio [(1-hct(2))/(1-hct(1))] of 1.14 +/- 0.02 was associated wi th a K ratio of 1.07 +/- 0.02 (P = .01). Only sinusoidal binding diseq uilibrium predicted this finding, whereas an additional unstirred wate r layer effect could not be excluded, The observations could be simula ted by a model that included both of these effects. Thus, neither the relative changes of K nor the absolute K values required the assumptio n of facilitated uptake from the bound pool. The parameter-free design presented may be useful with other ligands in intact animals.