RADIOLABELED METABOLITES OF PROTEINS PLAY A CRITICAL ROLE IN RADIOACTIVITY ELIMINATION FROM THE LIVER

We have recently reported that the behavior of radiolabeled metabolite s in the liver appears to be responsible for the hepatic radioactivity levels after administration of protein radiopharmaceuticals. To bette r understand the role played by radiolabeled metabolites in hepatic ra dioactivity levels, two benzyl-EDTA derivatives rendering different ra diolabeled metabolites, (4-isothiocyanatobenzyl)ethylenediaminetetraac etic acid (SCN-Bz-EDTA) and 1-[p-(5-maleimidopentyl)amino benzyl] ethy lenediaminetetraacetic acid (ECMS-Bz-EDTA), were selected as bifunctio nal chelating agents (BCAs), and In-111 labeling of galactosyl-neoglyc oalbumin (NGA) and mannosyl-neoglycoalbumin (NMA) was performed. Biodi stribution of radioactivity in mice and subcellular distribution of ra dioactivity in hepatocytes were then compared. After accumulation in h epatic parenchymal cells, NGA-EMCS-Bz-EDTA-In-111 rendered a faster el imination rate of radioactivity from the liver than NGA-SCN-Bz-EDTA-In -111. Although each In-111-NMA exhibited a delayed elimination rate of radioactivity from the liver compared to the In-111-NGA counterpart, NMA-EMCS-Bz-EDTA-In-111 showed faster elimination rate of radioactivit y than NMA-SCN-Bz-EDTA-In-111. Analyses of radioactivity excreted in f eces and urine and remaining in the liver indicated that both BCAs ren dered mono-amino acid adducts as the major radiolabeled metabolites (c ysteine-EMCS-Bz-EDTA-In-111 and lysine-SCN-Bz-EDTA-In-111), which were generated in both cell types of the liver within 1 h postinjection. S ubcellular distribution of radioactivity indicated that the radioactiv ity was copurified with lysosomes. These results demonstrate that alth ough in vivo stability of radiometal chelates is essential, the biolog ical properties of the radiolabeled metabolites generated after lysoso mal proteolysis in hepatocytes play a critical role in radioactivity e limination from the liver.