Two hydroxypyridinone-containing actinide decorporation agents, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), are being developed for the treatment of internal actinide contamination by chelation therapy. Dose-response efficacy profiles in mice were established for the removal of intravenously injected 238Pu and 241Am after parenteral and oral treatment with these chelators. In both cases, presumed efficacious doses promoted substantially greater actinide elimination rates than the currently approved agent, diethylenetriamine-pentaacetic acid, considering two different interspecies scaling methods for the conversion of human doses to equivalent rodent dose levels. In addition, genotoxicity of both ligands was assessed using the Salmonella/Escherichia coli/microsome plate incorporation test and the Chinese hamster ovary cell chromosome aberration assay, showing that neither ligand is genotoxic, in the presence and absence of metabolic activation. Finally, maximum tolerated dose studies were performed in rats for seven consecutive daily oral administrations with the chelators, confirming the safety of the presumed efficacious doses for 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO). The results of these studies add to the growing body of evidence that both decorporation agents have remarkable decorporation efficacy properties and promising safety toxicology profiles. These results are necessary components of the regulatory approval process and will help determine the optimal human dosing regimens for the treatment of internal radionuclide contamination.
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1 February 2013
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January 04 2013
Dose-Dependent Efficacy and Safety Toxicology of Hydroxypyridinonate Actinide Decorporation Agents in Rodents: Towards a Safe and Effective Human Dosing Regimen
Deborah I. Bunin;
Deborah I. Bunin
1
aBiosciences Division, SRI International, Menlo Park, California 94025
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Polly Y. Chang;
Polly Y. Chang
1
aBiosciences Division, SRI International, Menlo Park, California 94025
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Rupa S. Doppalapudi;
Rupa S. Doppalapudi
aBiosciences Division, SRI International, Menlo Park, California 94025
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Edward S. Riccio;
Edward S. Riccio
aBiosciences Division, SRI International, Menlo Park, California 94025
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Dahlia An;
Dahlia An
bChemical Sciences Division, The Glenn T. Seaborg Center, Lawrence Berkeley National Laboratory, Berkeley, California 94720
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Erin E. Jarvis;
Erin E. Jarvis
bChemical Sciences Division, The Glenn T. Seaborg Center, Lawrence Berkeley National Laboratory, Berkeley, California 94720
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Birgitta Kullgren;
Birgitta Kullgren
bChemical Sciences Division, The Glenn T. Seaborg Center, Lawrence Berkeley National Laboratory, Berkeley, California 94720
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Rebecca J. Abergel
Rebecca J. Abergel
2
bChemical Sciences Division, The Glenn T. Seaborg Center, Lawrence Berkeley National Laboratory, Berkeley, California 94720
2 Address for correspondence: Lawrence Berkeley National Laboratory, One Cyclotron Road, MS 70A-1150, Berkeley, CA 94720; e-mail: rjabergel@lbl.gov.
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Radiat Res (2013) 179 (2): 171–182.
Article history
Received:
June 30 2012
Accepted:
August 28 2012
Citation
Deborah I. Bunin, Polly Y. Chang, Rupa S. Doppalapudi, Edward S. Riccio, Dahlia An, Erin E. Jarvis, Birgitta Kullgren, Rebecca J. Abergel; Dose-Dependent Efficacy and Safety Toxicology of Hydroxypyridinonate Actinide Decorporation Agents in Rodents: Towards a Safe and Effective Human Dosing Regimen. Radiat Res 1 February 2013; 179 (2): 171–182. doi: https://doi.org/10.1667/RR3115.1
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