title: Biodistribution of the multidentate hydroxypyridinonate ligand [(14) C]-3,4,3-LI(1,2-HOPO), a potent actinide decorporation agent.
abstract: The 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.
authors: Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors: Taylor A
authors: TA
authors: Choi
authors: Biosciences Division, SRI International, Menlo Park, CA, USA.
authors: Aaron N
authors: AN
authors: Endsley
authors: Biosciences Division, SRI International, Menlo Park, CA, USA.
authors: Deborah I
authors: DI
authors: Bunin
authors: Biosciences Division, SRI International, Menlo Park, CA, USA.
authors: Christophe
authors: C
authors: Colas
authors: Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors: Dahlia D
authors: DD
authors: An
authors: Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors: Joel A
authors: JA
authors: Morales-Rivera
authors: Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors: Jonathan A
authors: JA
authors: Villalobos
authors: Biosciences Division, SRI International, Menlo Park, CA, USA.
authors: Walter M
authors: WM
authors: Shinn
authors: Biosciences Division, SRI International, Menlo Park, CA, USA.
authors: Jack E
authors: JE
authors: Dabbs
authors: Biosciences Division, SRI International, Menlo Park, CA, USA.
authors: Polly Y
authors: PY
authors: Chang
authors: Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
authors: Rebecca J
authors: RJ
authors: Abergel
mesh_terms: D008671:Actinoid Series Elements / Q000378:metabolism*; D000818:Animals; D002250:Carbon Radioisotopes / Q000737:chemistry / Q000378:metabolism*; D002614:Chelating Agents / Q000737:chemistry / Q000378:metabolism; D005260:Female; D008024:Ligands; D008297:Male; D008657:Metabolic Clearance Rate / Q000502:physiology; D051379:Mice; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism; D011728:Pyridones / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution / Q000502:physiology
chemical_list: D008671:Actinoid Series Elements; D002250:Carbon Radioisotopes; D002614:Chelating Agents; D008024:Ligands; D011725:Pyridines; D011728:Pyridones; C014047:hydroxypyridines; C546958:1-hydroxy-2(1H)-pyridinone
keywords: 3,4,3-LI(1,2-HOPO); actinide decorporation; biodistribution; metabolite; pharmacokinetics