TY - JOUR
T1 - Pharmacokinetics, protein binding and metabolism of a quinoxaline urea analog as an NF-κB inhibitor in mice and rats by LC-MS/MS
AU - Gautam, Nagsen
AU - Bathena, Sai Praneeth R.
AU - Chen, Qianyi
AU - Natarajan, Amarnath
AU - Alnouti, Yazen
N1 - Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 2013/7
Y1 - 2013/7
N2 - 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.
AB - 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.
KW - LC-MS/MS
KW - Metabolism
KW - NF-κB inhibitor 13-197
KW - Pharmacokinetics
KW - Protein binding
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U2 - 10.1002/bmc.2880
DO - 10.1002/bmc.2880
M3 - Article
C2 - 23483555
AN - SCOPUS:84878996440
VL - 27
SP - 900
EP - 909
JO - Biomedical Chromatography
JF - Biomedical Chromatography
SN - 0269-3879
IS - 7
ER -