KINETICS OF HEPATIC ACCUMULATION OF DEXTRANS IN ISOLATED-PERFUSED RATLIVERS

The role of various processes (uptake, release, metabolism, and excret ion) in the hepatic accumulation of dextrans was investigated in isola ted perfused rat livers (IPRLs). Single-pass IPRLs were infused with f luorescein-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 we re collected. In addition, two groups of livers were infused with FD-7 0 for 60 min, followed by 30 or 60 min of drug-free perfusion. The con centrations of the macromolecule in the samples were measured by a siz e exclusion chromatographic method. Similar, but limited, experiments were also conducted for FDs with MWs of 4,000 (FD-4) and 150,000 (FD-1 50). In addition, the metabolism of all three FDs were investigated us ing liver homogenates. Because of low hepatic extraction, the concentr ations of dextrans in the inlet and outlet perfusates were almost the same during the entire perfusion. However, liver concentrations increa sed almost linearly during the infusion of FD-70 (0-60 min) and declin ed slowly thereafter (60-120 min). The apparent hepatic extraction rat io (E-app) values, estimated directly from the concentrations of FDs i n 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 analysi s of experimental data, was 248 min. These studies define the role of various processes involved in the slow (but substantial) and MW depend ent hepatic accumulation of dextrans.