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Title: In Vitro Metabolism and Stability of the Actinide Chelating Agent 3,4,3-LI(1,2-HOPO)

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.
 [1] ;  [2] ;  [2] ;  [2] ;  [2] ;  [2] ;  [2] ;  [1]
  1. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Chemical Sciences Division
  2. SRI International, Menlo Park, CA (United States). Biosciences Division
Publication Date:
OSTI Identifier:
Grant/Contract Number:
AC02-05CH11231; HHSN272201000046C
Accepted Manuscript
Journal Name:
Journal of Pharmaceutical Sciences
Additional Journal Information:
Journal Volume: 104; Journal Issue: 5; Journal ID: ISSN 0022-3549
Research Org:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org:
Country of Publication:
United States
60 APPLIED LIFE SCIENCES; Chelation therapy; Stability; Microsomes; ADME; Protein binding; Cytochrome P450; Intestinal absorption