Pharmacokinetics, protein binding and metabolism of a quinoxaline urea analog as an NF‐κB inhibitor in mice and rats by LC‐MS/MS. (10th March 2013)

• Record Type: Journal Article
• Authors: Gautam, Nagsen; Bathena, Sai Praneeth R.; Chen, Qianyi; Natarajan, Amarnath; Alnouti, Yazen
• Is Part Of: Biomedical chromatography. Volume 27:Number 7(2013:Jul.)
• Page Start: 900
• Page End: 909
• Publication Date: 2013-03-10
• Subjects: LC‐MS/MS -- NF‐κB inhibitor 13–197 -- pharmacokinetics -- protein binding -- metabolism; Chromatographic analysis -- Periodicals; Biology -- Periodicals; Medicine -- Periodicals; Biology -- Periodicals; Chromatography -- methods -- Periodicals; Medicine -- Periodicals; 543.089
• DOI: 10.1002/bmc.2880
• Languages: English
• ISSNs: 0269-3879

Abstract

ABSTRACT: 13–197 is a novel NF‐ κ B inhibitor that shows promising in vitro efficacy data against pancreatic cancer. In this study, we characterized the pharmacokinetics, tissue distribution, protein binding and metabolism of 13–197 in mice and rats. A valid, sensitive and selective LC‐MS/MS method was developed. This method was validated for the quantification of 13–197, in the range of 0.1 or 0.2‐500 ng/mL in mouse plasma, liver, kidney, lung, heart, spleen, brain, urine and feces. 13–197 has low bioavailability of 3 and 16% in mice and rats, respectively. It has faster absorption in mice with 12‐fold shorter T max than in rats. Tissue concentrations were 1.3–69.2‐fold higher in mice than in rats at 72 h after intravenous administration. 13–197 is well distributed to the peripheral tissues and has relatively high tissue–plasma concentration ratios, ranging from 1.8 to 3634, in both mice and rats. It also demonstrated more than 99% binding to plasma proteins in both mice and rats. Finally, <1% of 13–197 is excreted unchanged in urine and feces, and metabolite profiling studies detected more than 20 metabolites in mouse and rat plasma, urine and feces, which indicates that 13–197 is extensively metabolized and primarily eliminated by metabolism rather than by excretion. Copyright © 2013 John Wiley & Sons, Ltd.