Arano Y, Mukai T, Akizawa H, Uezono T, Motonari H, Wakisaka K, Kairiyama C, Yokoyama A
Department of Radiopharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Nucl Med Biol. 1995 Jul;22(5):555-64. doi: 10.1016/0969-8051(95)00009-m.
We have recently reported that the behavior of radiolabeled metabolites in the liver appears to be responsible for the hepatic radioactivity levels after administration of protein radiopharmaceuticals. To better understand the role played by radiolabeled metabolites in hepatic radioactivity levels, two benzyl-EDTA derivatives rendering different radiolabeled metabolites, 1-(4-isothiocyanatobenzyl)ethylenediaminetetraacetic acid (SCN-Bz-EDTA) and 1-[p-(5-maleimidopentyl)aminobenzyl]ethylenediaminetetraacetic acid (ECMS-Bz-EDTA), were selected as bifunctional chelating agents (BCAs), and 111In labeling of galactosyl-neoglycoalbumin (NGA) and mannosyl-neoglycoalbumin (NMA) was performed. Biodistribution of radioactivity in mice and subcellular distribution of radioactivity in hepatocytes were then compared. After accumulation in hepatic parenchymal cells, NGA-EMCS-Bz-EDTA-111In rendered a faster elimination rate of radioactivity from the liver than NGA-SCN-Bz-EDTA-111In. Although each 111In-NMA exhibited a delayed elimination rate of radioactivity from the liver compared to the 111In-NGA counterpart, NMA-EMCS-Bz-EDTA-111In showed faster elimination rate of radioactivity than NMA-SCN-Bz-EDTA-111In. Analyses of radioactivity excreted in feces and urine and remaining in the liver indicated that both BCAs rendered mono-amino acid adducts as the major radiolabeled metabolites (cysteine-EMCS-Bz-EDTA-111In and lysine-SCN-Bz-EDTA-111In), which were generated in both cell types of the liver within 1 h postinjection. Subcellular distribution of radioactivity indicated that the radioactivity was copurified with lysosomes. These results demonstrate that although in vivo stability of radiometal chelates is essential, the biological properties of the radiolabeled metabolites generated after lysosomal proteolysis in hepatocytes play a critical role in radioactivity elimination from the liver.
我们最近报道，肝脏中放射性标记代谢物的行为似乎是蛋白质放射性药物给药后肝脏放射性水平的原因。为了更好地理解放射性标记代谢物在肝脏放射性水平中所起的作用，选择了两种产生不同放射性标记代谢物的苄基-EDTA衍生物，即1-(4-异硫氰酸苄基)乙二胺四乙酸(SCN-Bz-EDTA)和1-[对-(5-马来酰亚胺戊基)氨基苄基]乙二胺四乙酸(ECMS-Bz-EDTA)作为双功能螯合剂(BCAs)，并进行了111In标记半乳糖基新糖白蛋白(NGA)和甘露糖基新糖白蛋白(NMA)。然后比较了小鼠体内放射性的生物分布和肝细胞内放射性的亚细胞分布。在肝实质细胞中积累后，NGA-EMCS-Bz-EDTA-111In从肝脏中清除放射性的速率比NGA-SCN-Bz-EDTA-111In快。尽管与111In-NGA相比，每种111In-NMA从肝脏中清除放射性的速率都有所延迟，但NMA-EMCS-Bz-EDTA-111In显示出比NMA-SCN-Bz-EDTA-111In更快的放射性清除速率。对粪便和尿液中排泄的以及留在肝脏中的放射性进行分析表明，两种BCAs都产生单氨基酸加合物作为主要的放射性标记代谢物(半胱氨酸-EMCS-Bz-EDTA-111In和赖氨酸-SCN-Bz-EDTA-111In)，它们在注射后1小时内在肝脏的两种细胞类型中产生。放射性的亚细胞分布表明放射性与溶酶体共纯化。这些结果表明，尽管放射性金属螯合物的体内稳定性至关重要，但肝细胞溶酶体蛋白水解后产生的放射性标记代谢物的生物学特性在肝脏放射性清除中起关键作用。
