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Pharmacokinetic Characterization of Supinoxin and Its Physiologically Based Pharmacokinetic Modeling in Rats
- Source :
- Pharmaceutics, Pharmaceutics, Vol 13, Iss 373, p 373 (2021), Volume 13, Issue 3
- Publication Year :
- 2021
- Publisher :
- MDPI AG, 2021.
-
Abstract
- 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.
- Subjects :
- Volume of distribution
0303 health sciences
Physiologically based pharmacokinetic modelling
Chemistry
lcsh:RS1-441
Pharmaceutical Science
Adipose tissue
Absorption (skin)
Pharmacology
Article
Bioavailability
lcsh:Pharmacy and materia medica
phosphorylated p68
03 medical and health sciences
0302 clinical medicine
Pharmacokinetics
Oral administration
030220 oncology & carcinogenesis
physiologically based pharmacokinetic modeling
supinoxin
pharmacokinetics
Drug metabolism
030304 developmental biology
Subjects
Details
- ISSN :
- 19994923
- Volume :
- 13
- Database :
- OpenAIRE
- Journal :
- Pharmaceutics
- Accession number :
- edsair.doi.dedup.....1b25f794b4dfe48441952ef2bb5aae9a