HEPATIC-CLEARANCE MODELS - COMPARISON OF THE DISPERSION AND GORESKY MODELS IN OUTFLOW PROFILES FROM MULTIPLE INDICATOR DILUTION RAT-LIVER STUDIES

The multiple indicator dilution (MID) technique is often used for inve stigation of the kinetic behavior of substrates and metabolites in eli minating organs. The present study was a systematic comparison of the utility of the Goresky model (GM) (a structural model) and the mixed-b oundary dispersion model (DM) (a stochastic model) in the interpretati on of influx, efflux, and removal (sequestration) coefficients, with d ata generated from rat liver-perfusion/ MID studies. Although the GM a nd the DM are equivalent in their descriptions of membrane transport, they differ in their classifications of the dispersion of blood-borne elements. For the DM, the dispersion is an inverse Gaussian distributi on of vascular transit times; for the GM, it is accounted for by the d ispersion observed among noneliminated reference indicators (e.g. labe led red blood cells, albumin, sucrose, and H2O) or the derived referen ce. In this study, previously published rat liver-perfusion/MID data o btained for the glutathione conjugate of bromosulfophthalein and hippu ric acid, compounds that exhibit saturable carrier-mediated transport, with the GM were reanalyzed with the two-compartment DM, When the fit ted values for volume and transfer coefficients were compared, good co rrelation was found between the fitted vascular volume for the DM and the vascular volume for the reference indicator for the GM, The influx coefficients were generally similar between the models, but improved correspondence was observed when the DM was modified to include the la rge-vessel transit time. In contrast, the efflux and sequestration coe fficients obtained for the DM did not correspond well to those from th e GM, The disagreement was due, in part, to differences in the interpr etation of the late-in-time component of the reference transit time di stribution curve, which was not described well by the DM. Consequently , the residence time distribution and the relative dispersion were und erestimated by the DM.