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Biomedical sciences publications May 1, 2015

Biodistribution of the Multidentate Hydroxypyridinonate Ligand [(14) C]-3,4,3-Li(1,2-HOPO), a Potent Actinide Decorporation Agent

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Choi, T. A., Endsley, A. N., Bunin, D. I., Colas, C., An, D. D., Morales-Rivera, J. A., . . . Abergel, R. J. (2015). Biodistribution of the multidentate hydroxypyridinonate ligand [(14) C]-3,4,3-LI(1,2-HOPO), a potent actinide decorporation agent. Drug Development Research, 76(3), 107-122. doi: 10.1002/ddr.21246

Abstract

The pharmacokinetics and biodistribution of the 14C-labeled actinide decorporation agent 3,4,3-LI(1,2-HOPO) were investigated in young adult Swiss Webster mice and Sprague Dawley rats, after intravenous, intraperitoneal, and oral dose administration. In all routes investigated, the radiolabeled compound was rapidly distributed to various tissues and organs of the body. In mice, the 24 h fecal elimination profiles suggested that the biliary route is the predominant route of elimination. In contrast, lower fecal excretion levels were observed in rats. Tissue uptake and retention of the compound did not differ significantly between sexes although some differences were observed in the excretion patterns over time. The male mice eliminated a greater percentage of 14C through the renal pathway than the female mice after receiving an intravenous or intraperitoneal dose, while the opposite trend was seen in rats that received an intravenous dose. Metabolite profiling performed on selected rat samples demonstrated that a putative major metabolite of [14C]-3,4,3-LI(1,2-HOPO) is formed, accounting for approximately 10% of an administered oral dose. Finally, to improve its oral bioavailability, 3,4,3-LI(1,2-HOPO) was coformulated with a proprietary permeability enhancer, leading to a notable increase in oral bioavailability of the compound.

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