Abstract
Hepatic targeting of proteins utilizing the sugar -recognition system was investigated in mice after intravenous injection. Five proteins with different molecular weights, i.e., bovine γ-globulins(IgG), bovine serum albumin(BSA), recombinant human superoxide dismutase(SOD), soybean trypsin inhibitor(STI), and chicken egg white lysozyme(LZM) were selected and modified with 2-imino-2-methoxyethyl 1-thiogalactoside to obtain galactosylated proteins. All galactosylated proteins were dose-dependently taken up by the liver and the amounts accumulated in the liver were decreased with the increase of the administered dose. However, the hepatic clearances were greatly different among them. At doses less than 1 mg/kg, Gal-IgG, Gal-BSA, and Gal-SOD had large values of hepatic clearance close to the hepatic plasma flow (85 ml/hr) and those of Gal-STI and Gal-LZM were 40 and 20 ml/hr, respectively. Their hepatic uptake processes were analyzed by a physiologically pharmacokinetic model including the hepatic plasma flow and the saturable uptake process in the liver. This analysis based on a model revealed the low affinity to the carbohydrate receptors on hepatocytes and high glomerular filtration rate resulted the ineffective delivery of Gal-STI and Gal-LZM to the liver. These results suggested that galactosylation of proteins with molecular weight greater than that of SOD led them to be delivered to the liver at lower doses less than 1 mg/kg and that proteins with molecular weight less than that of SOD could not be effectively delivered to the liver by galactosylation because of their low affinity to the liver due to small numbers of attached galactose residues and high glomerular filtration rate.
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