Pharmacokinetic characterization of LW6, a novel hypoxia-inducible factor-1α (HIF-1α) inhibitor in mice

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Title
Pharmacokinetic characterization of LW6, a novel hypoxia-inducible factor-1α (HIF-1α) inhibitor in mice
Author(s)
J Y Lee; K Lee; K Lee; Jong Soon KangMin Ju Kim; D G Yoo; J A Kim; E J Shin; S J Oh
Bibliographic Citation
Molecules, vol. 26, no. 8, pp. 2226-2226
Publication Year
2021
Abstract
LW6, an (aryloxyacetylamino)benzoic acid derivative, was recently identified to be an inhibitor of hypoxia-inducible factor-1α (HIF-1α), which is an attractive target for cancer therapeutics. Although LW6 is known to act by inhibiting the accumulation of HIF-1α, pharmacokinetics needs to be evaluated to assess its potential as an anti-tumor agent. Here, we investigated the plasma pharmacokinetics and metabolism of LW6 in mice. LW6 exhibited a small volume of distribution (0.5 ± 0.1 L/kg), and a short terminal half-life (0.6 ± 0.1 h). Following intravenous or oral administration, LW6 was rapidly converted to its active metabolite, (4-adamantan-1-yl-phenoxy)acetic acid (APA). Although LW6 was rapidly absorbed, its oral bioavailability, estimated using AUClast values, was low (1.7 ± 1.8%). It was slowly degraded in mouse liver microsomes (t1/2 > 1 h) and serum (t1/2 > 6 h). About 54% or 44.8% of LW6 was available systemically as APA in the mouse after a single intravenous or oral administration, respectively. Thus, our results indicated the need to simultaneously consider the active metabolite as well as the parent compound for successful evaluation during lead optimization.
Keyword
LW6Mice pharmacokineticsLiver microsomesMetabolismCaco-2 cells
ISSN
1420-3049
Publisher
MDPI
DOI
http://dx.doi.org/10.3390/molecules26082226
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of Bioinfrastructure > Laboratory Animal Resource Center > 1. Journal Articles
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