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

Abstract

ABSTRACT: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.Despite the liver receiving a dual blood supply, the portal vein (PV) has been the main source of input for studying hepatic disposition using the isolated perfused liver preparation. Nevertheless, this approach is unphysiological in the sense that it excludes the possible contribution from the hepatic artery (HA). Studies concerned with the interaction of these two inputs suggest that both a common and specific space exists: the majority of the sinusoids are the common channels for both streams, whereas a small fraction (approximately 5-10%; Field and Andrews, 1968;Ahmad et al., 1984;Reichen, 1988;Kassissia et al., 1994;Pang et al., 1994;Sahin and Rowland, 1998b) remains specific to the HA. Although existing clearance data suggest that the difference between the PV and HA might be attributable to the presence of the specific arterial space (Ahmad et al., 1984;Pang et al., 1994;Sahin and Rowland, 2000b), they do not provide any information on the disposition characteristics of this space. However, this can be achieved by defining each space in a model. The axial dispersion model has its origins in chemical engineering (Kreft and Zuber, 1978), where it was developed to describe the mixing of substances on transport through a packed reactor bed. It was introduced into the field of pharmacokinetics by Roberts and Rowland (1986a,b,c) to describe the mixing events in the liver. They proposed that the branch p...

Canadian Content in the Pages ofDrug Metabolism and Disposition: A Comprehensive Historical Analysis

“…The group of Yun Tam, along with UAlberta colleagues, made extensive use of isolated perfused rat liver models to characterize the disposition kinetics of lidocaine Saville et al, 1987;Tam et al, 1987;Ngo et al, 1995;Zaman et al, 1996), diltiazem (Hussain et al, 1994b), and the kinetic interactions of lidocaine and other drugs with diltiazem (Hussain et al, 1994a). This group also developed a series-compartment model for the hepatic elimination of drugs .…”

Drug structure–transport relationships

“…This finding confirms that the dispersion number is a measure of the variation in residence times of solutes in the hepatic vasculature. In other studies, Malcolm’s group has examined hepatic disposition of salicylate [100], the effect of varying plasma [101, 102] and hepatic tissue binding [103], as well as the role of the dual liver blood supply [104] and erythrocyte binding [105] on hepatic disposition kinetics. My group’s work has taken a slightly different track and concentrated on solute structure-hepatic disposition relationships in normal and in diseased livers.…”