The isolated perfused rat liver preparation was employed to study hepatic disposition of the model drugcarrier conjugate fluorescein-lactosylated albumin (F-L.HSA) with special reference to the influence of the organic anion fluorescein on liver cell specificity of the endocytomd neoglycoprotein. Hepatic clearance of fluoreseehated neoglycoproteins was significantly faster than clearance of radioiodinated neoglycoproteins. Perfusate clearance of F-L,HSA and F-LzaHSA could not completely be inhibited by a dose of 10 mg asialmrosomucoid that saturates the hepatocyte receptor-mediated endocytic process. From these data, we inferred an additional hepatic uptake mechanism, competing with the Ashwell-receptor-mediated internalization of galactoseterminated glycoproteins. Clearance experiments with fluoresceinated 'zsI-human serum albumin in the presence of the polyanionic probe dextran sulfate revealed a nearly complete (-90%) inhibition of hepatic uptake, while also a pronounced effect WM obtained with colloidal carbon. These data point to nonparenchymal cell uptake of fluoresceinated protein via interaction with scavenger receptors. In wash-out studies, it was shown that about 25% of ligand sequestrated by sinusoidal liver cells escaped degradation and recycled to the perfusion medium. Our results show that care should be taken in the use of neoglycoproteins as drug carriers to hepatocytes, since a load of only 2 to 3 moles fluorescein per mole neoglycoprotein considerably affects intrahepatic distribution. The relative contribution of nonparenchymal cell uptake by coupling of acidic drugs to the neo- glycoproteins is very probably inversely related to the number of exposing galactose groups per molecule neoglycoprotein. This phenomenon of "inversed targeting" could therapeutically both be useful or detrimental, dependent on the spectrum of cell types that should be reached by the drug.
Mammalian hepatocytes possess a receptor specific for plasma glycoproteins with terminal p-D-galactose or Nacetyl-a-D-galactosamine residues (1). Interaction with