CONTROL OF IN-VIVO FATE OF ALBUMIN DERIVATIVES UTILIZING COMBINED CHEMICAL MODIFICATION

Three types of bovine serum albumin (BSA) derivatives such as lactosyl ated BSA (LBSA), mannosylated BSA (Man-BSA), and cationized BSA (cBSA) were synthesized and their hepatic disposition characteristics in mic e were evaluated by pharmacokinetic analysis. At lower doses (less-tha n-or-equal-to 1 mg/kg), LBSA and Man-BSA were very rapidly eliminated from the blood circulation due to uptake by parenchymal and nonparench ymal cells of the liver, respectively, via receptor-mediated endocytos is (Nishikawa et al., 1992; Nishida et al., 1991a, b). These uptake pr ocesses were nonlinear and the apparent hepatic uptake clearances (CL( liver)) were decreased at administered doses higher than 1mg/kg, e.g. 10, 20, and 100mg/kg. The liver accumulation of cBSA was also nonlinea r, but its binding and/or uptake capacity in the liver was larger than those of LBSA and Man-BSA; i.e., CL(liver) decreased at doses higher than 20 mg/kg. In the next step, we modified these BSA derivatives by attaching polyethylene glycol (PEG), a modifier known to reduce the he patic uptake and increase plasma retention, to achieve precise control of the in vivo disposition characteristics of BSA derivatives. By con jugation with PEG having a molecular weight of 10 kDa, the CL(liver) v alues of LBSA, Man-BSA, and cBSA were decreasing to one-seventh, one-f ortyfifth, and one-onehundredthirtieth, respectively. However, liver a ccumulation of PEG modified LBSA and ManBSA at 24h after i.v. injectio n was not significantly different from unmodified BSA derivatives. The se results suggest that it is possible to control the hepatic uptake o f protein drugs by a combination of introduction of charge or sugar mo ieties and PEG conjugation.