4.7 Article

Pharmacokinetic Characterization of Supinoxin and Its Physiologically Based Pharmacokinetic Modeling in Rats

期刊

PHARMACEUTICS
卷 13, 期 3, 页码 -

出版社

MDPI
DOI: 10.3390/pharmaceutics13030373

关键词

phosphorylated p68; supinoxin; pharmacokinetics; physiologically based pharmacokinetic modeling

资金

  1. National Research Fund of Korea [2017M3A9C8021844]
  2. Korea Research Institute of Bioscience and Biotechnology (KRIBB) Research Initiative Programs
  3. National Research Foundation of Korea [2017M3A9C8021844] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)

向作者/读者索取更多资源

Supinoxin, a novel anticancer drug candidate, exhibited good permeability and dose-independent pharmacokinetics in rats. After oral administration, it showed modest absorption and high absolute oral bioavailability, mainly eliminated via NADPH-dependent phase I metabolism.
Supinoxin is a novel anticancer drug candidate targeting the Y593 phospho-p68 RNA helicase, by exhibiting antiproliferative activity and/or suppression of tumor growth. This study aimed to characterize the in vitro and in vivo pharmacokinetics of supinoxin and attempt physiologically based pharmacokinetic (PBPK) modeling in rats. Supinoxin has good permeability, comparable to that of metoprolol (high permeability compound) in Caco-2 cells, with negligible net absorptive or secretory transport observed. After an intravenous injection at a dose range of 0.5-5 mg/kg, the terminal half-life (i.e., 2.54-2.80 h), systemic clearance (i.e., 691-865 mL/h/kg), and steady state volume of distribution (i.e., 2040-3500 mL/kg) of supinoxin remained unchanged, suggesting dose-independent (i.e., dose-proportional) pharmacokinetics for the dose ranges studied. After oral administration, supinoxin showed modest absorption with an absolute oral bioavailability of 56.9-57.4%. The fecal recovery following intravenous and oral administration was 16.5% and 46.8%, respectively, whereas the urinary recoveries in both administration routes were negligible. Supinoxin was mainly eliminated via NADPH-dependent phase I metabolism (i.e., 58.5% of total clearance), while UDPGA-dependent phase II metabolism appeared negligible in the rat liver microsome. Supinoxin was most abundantly distributed in the adipose tissue, gut, and liver among the nine major tissues studied (i.e., the brain, liver, kidneys, heart, lungs, spleen, gut, muscles, and adipose tissue), and the tissue exposure profiles of supinoxin were well predicted with physiologically based pharmacokinetics.

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