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Characterization of TPN171 metabolism in humans via ultra-performance liquid chromatography/quadrupole time-of-flight Checir for mass spectrometry

文献类型：期刊论文

作者Pan, Lulu1,3; Guo, Shuang2,3; Chen, Xiaoyan1,3; Jiang, Xiangrui2; Shen, Jingshan2; Diao, Xingxing1; Wang, Zhen2; Zhong, Dafang1,3
刊名JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
出版日期2019-08-05
卷号172页码:302-310
关键词TPNI71 Metabolism UPLC/Q-TOF MS High-resolution mass spectrometry Metabolite identification
ISSN号0731-7085
DOI10.1016/j.jpba.2019.05.001
通讯作者Diao, Xingxing(xxdiao@simm.ac.cn) ; Wang, Zhen(wangzhen@simm.ac.cn) ; Zhong, Dafang(dfzhong@simm.ac.cn)
英文摘要TPN171 is a novel potent pyrimidinone phosphodiesterase type 5 (PDE5) inhibitor with high selectivity and long duration of action. It has been used to treat patients suffering from pulmonary arterial hypertension and entered phase I clinical trials in 2016. Considering the potential therapeutic value of TPN171, its metabolism in humans is necessary to be elucidated during early-stage of drug development. This study aimed to establish a rapid and reliable method based on ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry for the characterization of TPN171 metabolites in human plasma, urine and stool samples. A total of 17 metabolites, including 14 from phase I and 3 from phase II metabolic reactions, were identified and characterized. TPN171 was found to be the predominant component in all plasma, urine and stool samples. Seven proposed metabolites were validated by comparing with synthetic reference standards. N-demethylation, O-depropylation, N-oxidation and dehydrogenation were demonstrated to be the main metabolic pathways of TPN171 in humans, yielding metabolites M4, M3, M7-2 and M5-3, respectively. Notably, M5-3 (a dehydrogenation product) and M3 (an O-depropylation product) were the main metabolites in human plasma while M5-3 (produced via dehydrogenation) and M7-2 (produced via N-oxidation) were the major metabolites in human urine. Besides, O-depropylation product M3 and N-demethylation product M4 were the main metabolites in human stool. In overall, this study assessed the metabolic fate of TPN171 in humans, which may yield considerably benefits for subsequent studies focusing on TPN171 metabolism and development of other PDE5 inhibitors. (C) 2019 Elsevier B.V. All rights reserved.
WOS关键词SILDENAFIL ; IDENTIFICATION ; HYPERTENSION ; INHIBITORS ; MS/MS ; RATS ; VIVO
资助项目Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12050306] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040103] ; National Natural Science Foundation of China[81521005] ; Vigonvita Life Science Co., Ltd.
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000470798500036
出版者ELSEVIER SCIENCE BV
源URL[http://119.78.100.183/handle/2S10ELR8/289567]  
专题新药研究国家重点实验室
通讯作者Diao, Xingxing; Wang, Zhen; Zhong, Dafang
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, 501 Haike Rd, Shanghai 201203, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Pan, Lulu,Guo, Shuang,Chen, Xiaoyan,et al. Characterization of TPN171 metabolism in humans via ultra-performance liquid chromatography/quadrupole time-of-flight Checir for mass spectrometry[J]. JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS,2019,172:302-310.
APA Pan, Lulu.,Guo, Shuang.,Chen, Xiaoyan.,Jiang, Xiangrui.,Shen, Jingshan.,...&Zhong, Dafang.(2019).Characterization of TPN171 metabolism in humans via ultra-performance liquid chromatography/quadrupole time-of-flight Checir for mass spectrometry.JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS,172,302-310.
MLA Pan, Lulu,et al."Characterization of TPN171 metabolism in humans via ultra-performance liquid chromatography/quadrupole time-of-flight Checir for mass spectrometry".JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS 172(2019):302-310.

入库方式： OAI收割

来源：上海药物研究所

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