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

• Published in: Molecules (Basel, Switzerland) Vol. 26; no. 8; p. 2226
• Main Authors: Lee, Ji-Yoon, Lee, Kiho, Lee, Kyeong, Kang, Jong Soon, Kim, Min Ju, Yoo, Dong Gu, Kim, Jung Ah, Shin, Eun Jin, Oh, Soo Jin
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 12-04-2021; MDPI
• Subjects: Acetanilides - blood; Acetanilides - metabolism; Acetanilides - pharmacokinetics; Acetanilides - pharmacology; Acetic acid; Adamantane - analogs & derivatives; Adamantane - blood; Adamantane - metabolism; Adamantane - pharmacokinetics; Adamantane - pharmacology; Animals; Benzoic acid; Bioavailability; Caco-2 Cells; Cancer; Cell Membrane Permeability - drug effects; Evaluation; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - antagonists & inhibitors; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factor 1a; Injections, Intravenous; Intravenous administration; Liver; liver microsomes; LW6; Male; Metabolism; Metabolites; Metabolome; Mice; mice pharmacokinetics; Mice, Inbred ICR; Microsomes; Microsomes, Liver - drug effects; Microsomes, Liver - metabolism; Optimization; Oral administration; Permeability; Pharmacokinetics; Pharmacology; Plasma; Time Factors; LW6; metabolism; Caco-2 cells; liver microsomes; mice pharmacokinetics
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules26082226

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
values, was low (1.7 ± 1.8%). It was slowly degraded in mouse liver microsomes (
> 1 h) and serum (
> 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.