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Application of the Dispersion Model to Describe Disposition Kinetics of Markers in the Dual Perfused Rat Liver

Faculty of Pharmacy, University of Hacettepe, Ankara, Turkey (S.S.); and School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester, United Kingdom (S.S., M.R.)

The liver receives two blood supplies, portal and hepatic, yet most in situ studies use only portal perfusion. A model based on dispersion principles was developed to provide baseline data of the dual perfused rat liver preparation by characterizing the temporal outflow profiles of noneliminated reference markers (vascular marker, red blood cells; extracellular markers, albumin, sucrose; and intracellular markers, urea, water). The model consists of two components: the common and a specific arterial space operating in parallel. The common space receives all the portal flow and some of the arterial flow; the remaining arterial flow perfuses the specific space. Each space is divided into three subspaces: vascular, interstitial, and intracellular. The extent of axial spreading of solute on passage through the common and specific spaces is characterized by their respective dispersion numbers, D_N. The model was fully characterized by analysis of the outflow data following independent bolus administration into the portal vein and hepatic artery. The model provided a good fit of the data for all reference compounds. The estimate of the fraction of the total space assigned to the specific arterial space varied from 4 to 11%, with a mean value of 9%. The estimated D_N was always small (<0.25) and tended to be greater for the common space (0.08–0.23) than the specific space (0.05–0.12). However, for each space, there was no significant difference in the D_N value among all reference markers; this is assumed to arise because all markers are reflecting a common feature, the heterogeneity of the microvasculature.