Pharmacokinetic evaluation of mannosylated bovine serum albumin as a liver cell-specific carrier: Quantitative comparison with other hepatotropic ligands

To assess the feasibility of mannosylated macromolecules as a liver-specific carrier system, hepatic uptake characteristics of mannosylated bovine serum albumin (Man-BSA) were pharmacokinetically investigated. After intravenous injection, In-111-Man(18)-BSA accumulated in the liver up to 70% of dose at 2 h; the endothelial cells and Kupffer cells contributed about 66% and 21% of the uptake, respectively. In single-pass perfusion experiments using rat liver at varying inflow concentrations (0.1-2.0 mu g/ml), In-111-Man(18)-BSA and In-111-Man(33)-BSA were continuously extracted by the liver and their extraction ratios decreased with the increasing inflow concentrations. The outflow curves of each In-111-Man-BSA at three concentrations were simultaneously fitted to a pharmacokinetic model including a binding to the cell surface and an internalization, by using a nonlinear regression program MULTI(RUNGE). The binding constant augmented with the increase in the number of mannose per BSA, whereas the internalization rate constant was quite comparable for both derivatives. The pharmacokinetic analysis has demonstrated that the uptake process of In-111-Man-BSA is characterized to possess fewer binding sites and a greater internalization rate in comparison with other liver-specific carriers such as galactosylated, succinylated and cationized BSAs, These results will provide useful information in designing drug targeting systems to the liver nonparenchymal cells via mannose receptors.