PHARMACOKINETIC ANALYSIS OF SCAVENGER RECEPTOR-MEDIATED UPTAKE OF ANIONIZED PROTEINS IN THE ISOLATED-PERFUSED RAT-LIVER

The hepatic uptake characteristics of In-111-labeled succinylated lyso zyme (Suc-LZM), superoxide dismutase (Suc-SOD), bovine serum albumin ( Suc-BSA), catalase (Suc-CAT), and maleylated SOD (Mal-SOD), BSA (Mal-B SA) were studied in rat liver perfusion experiments. During a single-p ass constant infusion mode, [In-111]Suc-BSA, [In-111]Suc-CAT, and [In- 111]Mal-BSA were significantly extracted while extraction of [In-111]S uc-LZM, [In-111]Suc-SOD, and [In-111]Mal-SOD were small, suggesting th e importance of molecular weight or total number of anionic charges pe r one protein molecule for the hepatic uptake of anionized proteins. T he extraction ratio at steady state (E-ss) for [In-111]Suc-BSA was sig nificantly decreased by co-administration of Mal-BSA or dextran sulfat e, which is known to be taken up via scavenger receptor, and NH4Cl, di nitrophenol, or cytochalasin B, suggesting that hepatic uptake of [In- 111]Suc-BSA proceeds via receptor-mediated endocytosis. The internaliz ation rate constant (k(int)) for [In-111]Suc-BSA was calculated to be 0.27 min(-1) in liver perfusion experiments using the acid-wash method . The outflow patterns of [In-111]Suc-BSA at various inflow concentrat ions were simultaneously fitted to a physiological one-organ pharmacok inetic model, in which the hepatic uptake was represented by division into the processes of binding to the cell surface and internalization, by the use of the MULTI (RUNGE) program. The obtained pharmacokinetic parameters (maximum binding amount X-infinity, binding constant K, an d internalization rate constant k(int)) for [In-111]Suc-BSA clearly ch aracterized the difference in their hepatic uptake mechanisms compared with lactosylated and cationized BSA. The present study has demonstra ted that large succinylated and maleylated proteins should be useful a s a carrier for the intracellular delivery of drugs specifically into the liver endothelial cells. (C) 1997 Elsevier Science B.V.