Abstract

The role of various processes (uptake, release, metabolism, and excretion) in the hepatic accumulation of dextrans was investigated in isolated perfused rat livers (IPRLs). Single-pass IPRLs were infused with fluorescein-dextran (FD) with a molecular weight (MW) of 70,000 (FD-70) for 15, 30, 45, or 60 min, and inlet and outlet samples and livers were collected. In addition, two groups of livers were infused with FD-70 for 60 min, followed by 30 or 60 min of drug-free perfusion. The concentrations of the macromolecule in the samples were measured by a size exclusion chromatographic method. Similar, but limited, experiments were also conducted for FDs with MWs of 4,000 (FD-4) and 150,000 (FD-150). In addition, the metabolism of all three FDs were investigated using liver homogenates. Because of low hepatic extraction, the concentrations of dextrans in the inlet and outlet perfusates were almost the same during the entire perfusion. However, liver concentrations increased almost linearly during the infusion of FD-70 (0–60 min) and declined slowly thereafter (60–120 min). The apparent hepatic extraction ratio (E_app) values, estimated directly from the concentrations of FDs in the liver, were MW dependent; E_app of FD-4 (0.124% ± 0.015%) was significantly (p < 0.05) less than that for FD-70 (0.677% ± 0.193%) or FD-150 (0.711% ± 0.022%). The metabolism and biliary excretion of all FDs were negligible during the perfusion time. The mean residence time of FD-70 in the liver, estimated by nonlinear regression analysis of experimental data, was 248 min. These studies define the role of various processes involved in the slow (but substantial) and MW dependent hepatic accumulation of dextrans.