In Vitro Metabolism and Stability of the Actinide Chelating Agent 3,4,3-LI(1,2-HOPO)
Abstract
We report that the hydroxypyridinonate ligand 3,4,3-LI(1,2-HOPO) is currently under development for radionuclide chelation therapy. The preclinical characterization of this highly promising ligand comprised the evaluation of its in vitro properties, including microsomal, plasma, and gastrointestinal fluid stability, cytochrome P450 inhibition, plasma protein binding, and intestinal absorption using the Caco-2 cell line. When mixed with active human liver microsomes, no loss of parent compound was observed after 60 minutes, indicating compound stability in the presence of liver microsomal P450. At the tested concentrations, 3,4,3-LI(1,2-HOPO) did not significantly influence the activities of any of the cytochromal isoforms screened. Thus, 3,4,3-LI(1,2-HOPO) is unlikely to cause drug-drug interactions by inhibiting the metabolic clearance of co-administered drugs metabolized by these enzymes. Plasma protein binding assays revealed that the compound is protein-bound in dogs and less extensively in rats and humans. In the plasma stability study, the compound was stable after 1 h at 37°C in mouse, rat, dog, and human plasma samples. Finally, a bi-directional permeability assay demonstrated that 3,4,3-LI(1,2-HOPO) is not permeable across the Caco-2 monolayer, highlighting the need to further evaluate the effects of various compounds with known permeability enhancement properties on the permeability of the ligand in future studies.
- Authors:
-
- Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Chemical Sciences Division
- SRI International, Menlo Park, CA (United States). Biosciences Division
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1257825
- Alternate Identifier(s):
- OSTI ID: 1358693
- Grant/Contract Number:
- AC02-05CH11231; HHSN272201000046C
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Pharmaceutical Sciences
- Additional Journal Information:
- Journal Volume: 104; Journal Issue: 5; Journal ID: ISSN 0022-3549
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; Chelation therapy; Stability; Microsomes; ADME; Protein binding; Cytochrome P450; Intestinal absorption
Citation Formats
Choi, Taylor A., Furimsky, Anna M., Swezey, Robert, Bunin, Deborah I., Byrge, Patricia, Iyer, Lalitha V., Chang, Polly Y., and Abergel, Rebecca J. In Vitro Metabolism and Stability of the Actinide Chelating Agent 3,4,3-LI(1,2-HOPO). United States: N. p., 2015.
Web. doi:10.1002/jps.24394.
Choi, Taylor A., Furimsky, Anna M., Swezey, Robert, Bunin, Deborah I., Byrge, Patricia, Iyer, Lalitha V., Chang, Polly Y., & Abergel, Rebecca J. In Vitro Metabolism and Stability of the Actinide Chelating Agent 3,4,3-LI(1,2-HOPO). United States. https://doi.org/10.1002/jps.24394
Choi, Taylor A., Furimsky, Anna M., Swezey, Robert, Bunin, Deborah I., Byrge, Patricia, Iyer, Lalitha V., Chang, Polly Y., and Abergel, Rebecca J. Fri .
"In Vitro Metabolism and Stability of the Actinide Chelating Agent 3,4,3-LI(1,2-HOPO)". United States. https://doi.org/10.1002/jps.24394. https://www.osti.gov/servlets/purl/1257825.
@article{osti_1257825,
title = {In Vitro Metabolism and Stability of the Actinide Chelating Agent 3,4,3-LI(1,2-HOPO)},
author = {Choi, Taylor A. and Furimsky, Anna M. and Swezey, Robert and Bunin, Deborah I. and Byrge, Patricia and Iyer, Lalitha V. and Chang, Polly Y. and Abergel, Rebecca J.},
abstractNote = {We report that the hydroxypyridinonate ligand 3,4,3-LI(1,2-HOPO) is currently under development for radionuclide chelation therapy. The preclinical characterization of this highly promising ligand comprised the evaluation of its in vitro properties, including microsomal, plasma, and gastrointestinal fluid stability, cytochrome P450 inhibition, plasma protein binding, and intestinal absorption using the Caco-2 cell line. When mixed with active human liver microsomes, no loss of parent compound was observed after 60 minutes, indicating compound stability in the presence of liver microsomal P450. At the tested concentrations, 3,4,3-LI(1,2-HOPO) did not significantly influence the activities of any of the cytochromal isoforms screened. Thus, 3,4,3-LI(1,2-HOPO) is unlikely to cause drug-drug interactions by inhibiting the metabolic clearance of co-administered drugs metabolized by these enzymes. Plasma protein binding assays revealed that the compound is protein-bound in dogs and less extensively in rats and humans. In the plasma stability study, the compound was stable after 1 h at 37°C in mouse, rat, dog, and human plasma samples. Finally, a bi-directional permeability assay demonstrated that 3,4,3-LI(1,2-HOPO) is not permeable across the Caco-2 monolayer, highlighting the need to further evaluate the effects of various compounds with known permeability enhancement properties on the permeability of the ligand in future studies.},
doi = {10.1002/jps.24394},
journal = {Journal of Pharmaceutical Sciences},
number = 5,
volume = 104,
place = {United States},
year = {Fri Feb 27 00:00:00 EST 2015},
month = {Fri Feb 27 00:00:00 EST 2015}
}
Free Publicly Available Full Text
Publisher's Version of Record
Other availability
Search WorldCat to find libraries that may hold this journal
Cited by: 15 works
Citation information provided by
Web of Science
Web of Science
Save to My Library
You must Sign In or Create an Account in order to save documents to your library.
Works referenced in this record:
Radiation countermeasure agents: an update
journal, December 2009
- Dumont, Francis; Roux, Antoine Le; Bischoff, Pierre
- Expert Opinion on Therapeutic Patents, Vol. 20, Issue 1
Priority List of Research Areas for Radiological Nuclear Threat Countermeasures
journal, January 2005
- Pellmar, Terry C.; Rockwell, Sara
- Radiation Research, Vol. 163, Issue 1
Current and future radionuclide speciation studies in biological media
journal, June 2007
- Ansoborlo, E.; Bion, L.; Doizi, D.
- Radiation Protection Dosimetry, Vol. 127, Issue 1-4
Biomimetic Actinide Chelators: an Update on the Preclinical Development of the Orally Active Hydroxypyridonate Decorporation Agents 3,4,3-Li(1,2-Hopo) and 5-Lio(Me-3,2-Hopo)
journal, January 2010
- Abergel, Rebecca J.; Durbin, Patricia W.; Kullgren, Birgitta
- Health Physics, Vol. 99, Issue 3
Medical Countermeasures against Nuclear Threats: Radionuclide Decorporation Agents
journal, October 2008
- Cassatt, David R.; Kaminski, Joseph M.; Hatchett, Richard J.
- Radiation Research, Vol. 170, Issue 4
Dose-Dependent Efficacy and Safety Toxicology of Hydroxypyridinonate Actinide Decorporation Agents in Rodents: Towards a Safe and Effective Human Dosing Regimen
journal, February 2013
- Bunin, Deborah I.; Chang, Polly Y.; Doppalapudi, Rupa S.
- Radiation Research, Vol. 179, Issue 2
Significance of Single Variables in Defining Adequate Animal Models to Assess the Efficacy of New Radionuclide Decorporation Agents: Using the Contamination Dose as an Example: Animal Models for Chelating Agents Efficacy
journal, August 2012
- Jarvis, Erin E.; An, Dahlia D.; Kullgren, Birgitta
- Drug Development Research, Vol. 73, Issue 5
Validation and application of Caco-2 assays for the in vitro evaluation of development candidate drugs as substrates or inhibitors of P-glycoprotein to support regulatory submissions
journal, August 2008
- Elsby, R.; Surry, D. D.; Smith, V. N.
- Xenobiotica, Vol. 38, Issue 7-8
A micro-biuret method for estimating proteins
journal, December 1964
- Itzhaki, Ruth F.; Gill, D. M.
- Analytical Biochemistry, Vol. 9, Issue 4
Comparison of the acid stability of azithromycin and erythromycin A
journal, January 1990
- Fiese, E. F.; Steffen, S. H.
- Journal of Antimicrobial Chemotherapy, Vol. 25, Issue suppl A
Solution Stability - Plasma, Gastrointestinal, Bioassay
journal, November 2008
- Di, Li; Kerns, Edward
- Current Drug Metabolism, Vol. 9, Issue 9
Differences in the stability of prostacyclin in human, rabbit and rat plasma
journal, February 1983
- El Tahir, K. E. H.; Williams, K. I.; Betteridge, D. J.
- Prostaglandins, Leukotrienes and Medicine, Vol. 10, Issue 2
Works referencing / citing this record:
The toxicological mechanisms and detoxification of depleted uranium exposure
journal, May 2018
- Yue, Yong-Chao; Li, Ming-Hua; Wang, Hai-Bo
- Environmental Health and Preventive Medicine, Vol. 23, Issue 1
The toxicological mechanisms and detoxification of depleted uranium exposure
journal, May 2018
- Yue, Yong-Chao; Li, Ming-Hua; Wang, Hai-Bo
- Environmental Health and Preventive Medicine, Vol. 23, Issue 1