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Biodistribution of the Multidentate Hydroxypyridinonate Ligand [ 14 C]‐3,4,3‐LI(1,2‐HOPO), a Potent Actinide Decorporation Agent
Author(s) -
Choi Taylor A.,
Endsley Aaron N.,
Bunin Deborah I.,
Colas Christophe,
An Dahlia D.,
MoralesRivera Joel A.,
Villalobos Jonathan A.,
Shinn Walter M.,
Dabbs Jack E.,
Chang Polly Y.,
Abergel Rebecca J.
Publication year - 2015
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.21246
Subject(s) - biodistribution , pharmacokinetics , bioavailability , pharmacology , chemistry , metabolite , excretion , active metabolite , oral administration , medicine , biochemistry , in vitro
Preclinical ResearchThe pharmacokinetics and biodistribution of the 14 C‐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 14 C 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 [ 14 C]‐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. Drug Dev Res 73 : 107–122, 2015. © 2015 Wiley Periodicals, Inc.