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Pharmacokinetic Characterization of LW6, a Novel Hypoxia-Inducible Factor-1 alpha (HIF-1 alpha) Inhibitor in Mice

Authors
Lee, Ji-YoonLee, KihoLee, KyeongKang, Jong SoonKim, Min JuYoo, Dong GuKim, Jung AhShin, Eun JinOh, Soo Jin
Issue Date
4월-2021
Publisher
MDPI
Keywords
LW6; mice pharmacokinetics; liver microsomes; metabolism; Caco-2 cells
Citation
MOLECULES, v.26, no.8
Indexed
SCIE
SCOPUS
Journal Title
MOLECULES
Volume
26
Number
8
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/128331
DOI
10.3390/molecules26082226
ISSN
1420-3049
Abstract
LW6, an (aryloxyacetylamino)benzoic acid derivative, was recently identified to be an inhibitor of hypoxia-inducible factor-1 alpha (HIF-1 alpha), which is an attractive target for cancer therapeutics. Although LW6 is known to act by inhibiting the accumulation of HIF-1 alpha, 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 AUC(last) values, was low (1.7 +/- 1.8%). It was slowly degraded in mouse liver microsomes (t(1/2) > 1 h) and serum (t(1/2) > 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.
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약학대학 (약학과)
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