In vitro metabolism and stability of the actinide chelating agent 3,4,3-LI(1,2-HOPO)

Journal of Pharmaceutical Sciences
Taylor A ChoiRebecca J Abergel

Abstract

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 min, 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 coadministered 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 bidirectional permeability assay demonstrated that 3,4,3-LI(1,2-HOPO) is not permeable across the Caco-2 monol...Continue Reading

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Citations

Jul 7, 2015·Advanced Drug Delivery Reviews·Elias FattalGuillaume Phan
Aug 25, 2017·Nature Chemistry·Gauthier J-P DeblondeRebecca J Abergel
May 18, 2018·Environmental Health and Preventive Medicine·Yong-Chao YueWei He
Aug 7, 2020·Journal of Environmental Radioactivity·Yonghong RanYuhui Hao
Oct 3, 2019·Inorganic Chemistry·Florian LahrouchChristophe Di Giorgio

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