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
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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采用超高效液相色谱与四极杆飞行时间质谱联用对潜在抗肥胖化合物 3-甲基-1H-嘌呤-2,6-二酮衍生物 C-11 的体内代谢物进行表征
DOI：
10.1007/s10337-016-3097-x
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发表时间：
2016-05
期刊：
影响因子：
1.7
通讯作者：
Chen Lijuan
中科院分区：
文献类型：
--
作者：
Wang Hairong;Li Xiaobin;Ye Haoyu;Qiu Neng;Ma Liang;Wang Chunyu;Yang Qiunan;Tang Minghai;Wan Li;Chen Lijuan
C-11（2-（（7-乙基-3-甲基-8-（4-（2-（甲基（吡啶-2-基）-氨基）-乙氧基）苯基）-2，6-二氧代-2，3，6，7-四氢-1H-嘌呤-1-基）甲基）苯甲腈酮盐酸盐）是本实验室首次合成的，其结构与罗格列酮相似，是一种很有前途的抗肥胖药物。考虑到在早期药物发现过程中在体内代谢命运在候选药物的进一步开发中的重要性，表征C-11在体内的代谢是至关重要的。本研究建立了超高效液相色谱-四极杆飞行时间质谱联用技术（UPLC/Q-TOF-MS）研究C-11在大鼠体内代谢的方法。雄性Sprague-Dawley大鼠单次静脉给予30 mg/kg体重的C-11后，采集大鼠尿液、粪便和血浆样品。除母体药物外，共检测到25种代谢产物（包括18种I相代谢产物和7种II相代谢产物），并通过与C-11的质谱图谱比较初步鉴定。这使得C-11的代谢途径首次被提出。我们的研究结果表明，N-脱吡啶基化，N-去甲基化，羟基化，葡萄糖醛酸化和硫酸结合是C-11在大鼠体内的主要代谢途径。本研究提供了关于C-11在体内代谢的系统信息，这将有助于更好地了解其安全性和作用机制。
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−1body 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 thatN-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.
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DOI：
10.1016/j.jchromb.2012.08.015
发表时间：
2012-10-01
影响因子：
3
作者：
Lee, Soo Hyun;Yang, Hyun Ok;Jung, Byung Hwa
通讯作者：
Jung, Byung Hwa
影响因子：
2
作者：
Plumb, RS;Stumpf, CL;Dear, GJ
通讯作者：
Dear, GJ
影响因子：
6.1
作者：
Kwang-Hyeon Liu;J. Moon;Seung-Hun Kang;S. Koo;H. Lee;Jeong-Han Kim
通讯作者：
Kwang-Hyeon Liu;J. Moon;Seung-Hun Kang;S. Koo;H. Lee;Jeong-Han Kim
影响因子：
1.7
作者：
Dandan Li;Rui Xue;Zhi-xiong Li;Ming-cang Chen;Weixin Jiang;Chenggang Huang
通讯作者：
Dandan Li;Rui Xue;Zhi-xiong Li;Ming-cang Chen;Weixin Jiang;Chenggang Huang
影响因子：
1.8
作者：
Ning Li;Xuliang Wang;Ting-ting Li;H. Ji;Yihua Zhang;Zhixia Qiu;Di Zhao;Xijing Chen
通讯作者：
Ning Li;Xuliang Wang;Ting-ting Li;H. Ji;Yihua Zhang;Zhixia Qiu;Di Zhao;Xijing Chen