Characterization of TPN729 metabolites in humans using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry

doi:10.1016/j.jpba.2015.09.001

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	Characterization of TPN729 metabolites in humans using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry
	Zhu, Yunting; Li, Liang; Deng, Pan; Chen, Xiaoyan; Zhong, Dafang
刊名	JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
	2016-01-05
卷号	117 页码:217-226
关键词	TPN729 UPLC/Q-TOF MS Metabolite identification Metabolic pathways Human Sildenafil
ISSN号	0731-7085
DOI	10.1016/j.jpba.2015.09.001
文献子类	Article
英文摘要	TPN729 has been reported as a novel phosphodiesterase type 5 (PDE5) inhibitor to treat erectile dysfunction, and is currently being tested in clinical trials. In addition to the potent inhibition against PDE5, TPN729 is regarded as a better alternative to provide fewer side effects and better patient compliance. Given the potential therapeutic benefits of TPN729, it is of great importance to elucidate its metabolic characteristics in drug development. This study is the first to investigate the metabolic fate of TPN729 in humans. A rapid and reliable analytical method based on ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS) was established to investigate the metabolic profiles of TPN729 in human plasma, urine, and feces after its oral administration. As a result, a total of 22 metabolites were identified, of which seven were confirmed in comparison with the reference substances. The incubations of the metabolite references in human hepatocytes and aldehyde trapping experiment were further conducted to investigate its metabolic pathways. The results of the present study indicated the extensive metabolism of TPN729 in humans, including oxidative deamination, oxidative ring opening, N-dealkylation, N-oxidation, hydroxylation, dehydrogenation, lactam formation, and glucuronidation. M3 resulting from N-dealkylation was the major circulating substance detected in human plasma. The principal metabolites detected in human feces were products of oxidative deamination and oxidative ring opening. The parent drug was identified as the major component in urine. Taken together, this study provided valuable information on the metabolic fate of TPN729 in humans, and applicable analytical strategies for rapid metabolic elucidation in complex matrix samples through the useful and reliable UPLC/Q-TOF MS technique. (C) 2015 Elsevier B.V. All rights reserved.
WOS关键词	LIVER-MICROSOMES ; IDENTIFICATION ; SILDENAFIL ; DRUG ; RATS ; INHIBITORS ; MOUSE ; VIVO ; DOG
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER SCIENCE BV
WOS记录号	WOS:000365145500027
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/276183]
专题	上海药物代谢研究中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Zhong, Dafang
作者单位	Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
推荐引用方式 GB/T 7714	Zhu, Yunting,Li, Liang,Deng, Pan,et al. Characterization of TPN729 metabolites in humans using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry[J]. JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS,2016,117:217-226.
APA	Zhu, Yunting,Li, Liang,Deng, Pan,Chen, Xiaoyan,&Zhong, Dafang.(2016).Characterization of TPN729 metabolites in humans using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry.JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS,117,217-226.
MLA	Zhu, Yunting,et al."Characterization of TPN729 metabolites in humans using ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry".JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS 117(2016):217-226.