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-ĸB inhibitor that shows promising in-vitro efficacy data against pancreatic cancer. In this study, we characterized the pharmacokinetics (PK), 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 0.1–500 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. 13–197 has faster absorption in mice with 12-fold shorter Tmax than in rats. Tissue concentrations were 1.3–69.2 folds 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. 13–197 also demonstrated more than 99% binding to plasma proteins in both mice and rats. Finally, less than 1% of 13–197 is excreted unchanged in urine and feces, and metabolite profiling studies detected more than 20 metabolites in mice and rats plasma, urine, and feces, which indicates 13–197 is extensively metabolized and primarily eliminated by metabolism rather than by excretion.

Novel Treatment for Mantle Cell Lymphoma Including Therapy-Resistant Tumor by NF-κB and mTOR Dual-Targeting Approach

“…1A. The toxicity and pharmacokinetics (PK)-properties of this compound has been reported by Gautam, et al (39). IC 50 of 13-197 in different MCL cell lines are described in supplementary Table 1.…”

“…for 30 consecutive days. The dose of 13-197 for the treatment of mice was achieved from the reports described previously (28, 39). The dose and schedule for 13-197 were well tolerated.…”

“…Their study shows that 13-197 targets IKKβ and inhibits NF-κB and mTOR signaling pathways in pancreatic cancer cell lines. Regarding toxicity and pharmacokinetics properties of 13-197, Gautam et al (39) have shown that 13-197 does not have significant toxicity to normal tissues of mice and rats.…”

Bioanalytical method development and validation of moxidectin in plasma by LC–MS/MS: Application to in vitro metabolism

“…The in‐vitro metabolism studies were performed utilizing human liver S9 fractions (XenoTech, LLC, Lenexa, KS, USA) for both phase I and phase II metabolism. The incubation was performed as described and all analyses were performed in triplicate (Gautam, Bathena, Chen, Natarajan, & Alnouti, ; Gautam, Thakare, Rana, Natarajan, & Alnouti, ; Krishnaiah et al, ). The in vitro metabolic stability of MOX was determined using human liver S9 fractions following standard protocols.…”

Irreversible binding of an anticancer compound (BI-94) to plasma proteins

“…These techniques can be divided into methods that determine unbound concentration of drugs from which the bound concentration is indirectly estimated, and methods that directly determine bound concentrations of drugs (Yan & Caldwell, 2004). Commonly used methods in the first category include ultrafiltration, blood partitioning, equilibrium dialysis, chromatography using protein immobilized columns, ultracentrifugation, charcoal adsorption, high performance frontal analysis, solid phase microextraction, fluorescence, surface plasmon resonance, and solid supported lipid membranes (Ballard & Rowland, 2011; Banker & Clark, 2008; Barre et al, 1985; Chuang et al, 2009; Gautam et al, 2013; Howard et al, 2010; Schuhmacher et al, 2004; Shibukawa et al, 1999; Yuan et al, 1995). …”