In vitro metabolism and stability of the actinide chelating agent 3,4,3-LI(1,2-HOPO).
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 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.
Chemical Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California.
Taylor A
TA
Choi
Anna M
AM
Furimsky
Robert
R
Swezey
Deborah I
DI
Bunin
Patricia
P
Byrge
Lalitha V
LV
Iyer
Polly Y
PY
Chang
Rebecca J
RJ
Abergel
D008671:Actinoid Series Elements / Q000378:metabolism*; D000818:Animals; D018938:Caco-2 Cells; D002614:Chelating Agents / Q000737:chemistry* / Q000378:metabolism*; D004285:Dogs; D004355:Drug Stability; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D011728:Pyridones / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats
C000594124:1,5,10,14-tetra(1-hydroxy-2-pyridon-6-oyl)-1,5,10,14-tetraazatetradecane; D008671:Actinoid Series Elements; D002614:Chelating Agents; D006573:Heterocyclic Compounds, 1-Ring; D011728:Pyridones
ADME; chelation therapy; cytochrome P450; intestinal absorption; microsomes; protein binding; stability