Pharmacokinetics, protein binding and metabolism of a quinoxaline urea analog as an NF-κB inhibitor in mice and rats by LC-MS/MS

Nagsen Gautam, Sai Praneeth R. Bathena, Qianyi Chen, Amarnath Natarajan, Yazen Alnouti

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

13-197 is a novel NF-κB 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 0.2-500ng/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 Tmax than in rats. Tissue concentrations were 1.3-69.2-fold higher in mice than in rats at 72h 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.

Original languageEnglish (US)
Pages (from-to)900-909
Number of pages10
JournalBiomedical Chromatography
Volume27
Issue number7
DOIs
StatePublished - Jul 2013

Keywords

  • LC-MS/MS
  • Metabolism
  • NF-κB inhibitor 13-197
  • Pharmacokinetics
  • Protein binding

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biochemistry
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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