Characterization of In Vivo Metabolites of a Potential Anti-obesity Compound, the 3-Methyl-1H-Purine-2,6-Dione Derivative C-11, Employing Ultra-High Performance Liquid Chromatography Coupled with Quadrupole Time-of-Flight Mass Spectrometry
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- 作者：Hairong Wang ; Xiaobin Li ; Haoyu Ye ; Neng Qiu ; Liang Ma ; Chunyu Wang…
- 刊名：Chromatographia
- 出版年：2016
- 出版时间：June 2016
- 年：2016
- 卷：79
- 期：11-12
- 页码：693-702
- 全文大小：1,362 KB
- 刊物类别：Chemistry and Materials Science
- 刊物主题：Chemistry
Analytical Chemistry
Organic Chemistry
Pharmacy
Biochemistry
Plant Sciences
Measurement Science and Instrumentation - 出版者：Vieweg Verlag
- ISSN：1612-1112
- 卷排序：79
文摘
C-11 (2-((7-Ethyl-3-methyl-8-(4-(2-(methyl(pyridin-2-yl)-amino)-ethoxy)phenyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)methyl)benzonitrile-one hydrochloride), which is based on the structure of rosiglitazone, was first synthesized in our laboratory and shown to be a promising anti-obesity drug candidate in our previous pharmacological study. Considering the importance of metabolic fate in vivo in the further development of drug candidates during early drug discovery, it is essential to characterize the metabolism of C-11 in vivo. In this work, a method based on ultra-high performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS) was successfully developed to investigate the in vivo metabolic profile of C-11 in rats. Rat urine, feces, and plasma samples were collected from male Sprague–Dawley rats after intravenous administration of C-11 in a single dose of 30 mg kg−1 body weight. Besides the parent drug, a total of 25 metabolites (including 18 phase I and 7 phase II metabolites) were detected and tentatively identified by comparing their mass spectrometry profiles with those of C-11. This enabled the metabolic pathways of C-11 to be proposed for the first time. Our results revealed that N-depyridinylation, N-demethylation, hydroxylation, glucuronidation, and sulfate conjugation are the predominant metabolic pathways of C-11 in rats. The present study provides systematic information on the metabolism of C-11 in vivo, which should lead to a better understanding of its safety and mechanism of action.KeywordsC-11UPLC/Q-TOF-MSMetabolites in vivoMetabolic pathways