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

Molecules

Kyeong Lee¹  Ji-Yoon Lee²  SooJin Oh²  JungAh Kim³  DongGu Yoo³  EunJin Shin³  Kiho Lee⁴  JongSoon Kang⁵  MinJu Kim⁵ 

[1] BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University—Seoul, Goyang 10326, Korea;Convergence Medical Research Center, Asan Institute for Life Science, Asan Medical Center, Seoul 05505, Korea;Department of Medical Science, Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;Department of Pharmacy, College of Pharmacy, Korea University, Sejong 30019, Korea;Laboratory Animal Resource Center, KRIBB, Chungbuk 28116, Korea;

关键词: LW6;    mice pharmacokinetics;    liver microsomes;    metabolism;    Caco-2 cells;   

DOI  :  10.3390/molecules26082226

来源: DOAJ

【 摘 要 】

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 hr). 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_lastvalues, was low (1.7 ± 1.8 %). It was slowly degraded in mouse liver microsomes (t_1/2 > 1 hr) and serum (t_1/2 > 6 hr). 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.

【 授权许可】

Unknown