title: Pharmacokinetics, protein binding and metabolism of a quinoxaline urea analog as an NF-κB inhibitor in mice and rats by LC-MS/MS.
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 0.2-500 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 Tmax 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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, USA.
authors.forename: Nagsen
authors.initials: N
authors.lastname: Gautam
authors.forename: Sai Praneeth R
authors.initials: SP
authors.lastname: Bathena
authors.forename: Qianyi
authors.initials: Q
authors.lastname: Chen
authors.forename: Amarnath
authors.initials: A
authors.lastname: Natarajan
authors.forename: Yazen
authors.initials: Y
authors.lastname: Alnouti
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid / Q000379:methods*; D005243:Feces / Q000737:chemistry; D016014:Linear Models; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000032:analysis / Q000378:metabolism* / Q000493:pharmacokinetics*; D011485:Protein Binding; D011810:Quinoxalines / Q000008:administration & dosage / Q000032:analysis / Q000378:metabolism* / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D053719:Tandem Mass Spectrometry / Q000379:methods*; D014018:Tissue Distribution
chemical_list: C584232:13-197 compound; D016328:NF-kappa B; D010671:Phenylurea Compounds; D011810:Quinoxalines