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 among mammals after injection of protein radiopharmaceuticals, the metabolism of radiolabeled proteins and the fate of their radiometabolites in the parenchymal cells of rat liver were investigated and compared with those of mice. We used galactosyl-neoglycoalbumin (NGA) as a carrier protein, and NGA was labeled with 111In via 1-(4-isothiocyanatobenzyl)ethylenediaminetetraacetic acid (SCN-Bz-EDTA) or 1-[p-(5-maleimidopentyl)aminobenzyl]ethylenediaminetetraacetic acid (EMCS-Bz-EDTA) and with 125I via direct iodination. All radiolabeled NGAs exhibited rapid accumulation in liver parenchymal cells after intravenous injection into rats. Radioactivity was eliminated following NGA-125I injection at similar rates from rat and mouse liver. In contrast, both 111In-labeled NGAs demonstrated much slower elimination of radioactivity in rat when compared with mouse liver. Analyses of radioactivity in bile and liver indicated that both SCN-Bz-EDTA and EMCS-Bz-EDTA rendered mono-amino acid adducts as the final radiometabolites, which were generated 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 difference between rats and mice in radioactivity elimination from liver parenchymal cells would be predominantly attributable to the different efflux rate of the 111In-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 levels of radiolabeled proteins between animal and clinical studies.
Mukai
T
T
School of Pharmaceutical Sciences, Nagasaki University, Japan. mukai@net.nagasaki-u.ac.jp
Arano
Y
Y
Nishida
K
K
Sasaki
H
H
Akizawa
H
H
Ogawa
K
K
Ono
M
M
Saji
H
H
Nakamura
J
J
D000418:Albumins / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000493:pharmacokinetics*; D002614:Chelating Agents / Q000737:chemistry; D002845:Chromatography; D004492:Edetic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D007205:Indium Radioisotopes / Q000737:chemistry; D017879:Isothiocyanates / Q000737:chemistry; D008099:Liver / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008297:Male; D008301:Maleimides / Q000737:chemistry; D051379:Mice; D019275:Radiopharmaceuticals / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity
D000418:Albumins; D002352:Carrier Proteins; D002614:Chelating Agents; D007205:Indium Radioisotopes; D017879:Isothiocyanates; D008301:Maleimides; D019275:Radiopharmaceuticals; C064861:galactosyl-neoglycoalbumin; C119668:isothiocyanobenzyl ethylenediamine tetracetic acid; C096784:1-(4-(5-maleimidopentyl)aminobenzyl)ethylenediaminetetraacetic acid; D004492:Edetic Acid