Species difference in radioactivity elimination from liver parenchymal cells after injection of radiolabeled proteins

To elucidate the cause for the different levels of hepatic radioactivity am ong mammals after injection of protein radiopharmaceuticals, the metabolism of radiolabeled proteins and the fate of their radiometabolites in the par enchymal cells of rat liver were investigated and compared with those of mi ce. We used galactosyl-neoglycoalbumin (NGA) as a carrier protein, and NGA was labeled with In-111 via 1-(4-isothiocyanatobenzyl)ethylenediaminetetraa cetic acid (SCN-Bz-EDTA) or 1-[p-(5-maleimidopentyl) aminobenzyl]ethylenedi aminetetraacetic acid (EMCS-Bz-EDTA) and with I-125 via direct iodination. All radiolabeled NGAs exhibited rapid accumulation in liver parenchymal cel ls after intravenous injection into rats. Radioactivity was eliminated foll owing NGA-I-125 injection at similar rates from rat and mouse liver. In con trast, both In-111-labeled NGAs demonstrated much slower elimination of rad ioactivity in rat when compared with mouse liver. Analyses of radioactivity in bile and liver indicated that both SCN-Bz-EDTA and EMCS-Bz-EDTA rendere d mono amino acid adducts as the final radiometabolites, which were generat ed in rat liver within 1 h postinjection. Subcellular distribution studies suggested that these radiometabolites were copurified with lysosome in rat liver. Because similar results were observed in mice previously, the differ ence between rats and mice in radioactivity elimination from liver parenchy mal cells would be predominantly attributable to the different efflux rate of the In-111-labeled metabolites from the lysosome between these species. Such differences in the efflux rates of radiometabolites from the lysosome among mammals may also account for the different hepatic radioactivity leve ls of radiolabeled proteins between animal and clinical studies. NUCL MED B IOL 26;3:281-289, 1999. (C) 1999 Elsevier Science Inc. All rights reserved.