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	Metabolic characterization of pyrotinib in humans by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry
	Zhu, Yunting1,2; Li, Liang1; Zhang, Ge3; Wan, Hong3; Yang, Changyong3; Diao, Xingxing1; Chen, Xiaoyan1; Zhang, Lianshan3; Zhong, Dafang1
刊名	Journal of chromatography b-analytical technologies in the biomedical and life sciences
	2016-10-15
卷号	1033页码:117-127
关键词	Pyrotinib Uplc/q-tof ms Metabolism Human Cyp3a4 Drug-drug interaction
ISSN号	1570-0232
DOI	10.1016/j.jchromb.2016.08.009
通讯作者	Zhong, dafang(dfzhong@simm.ac.cn)
英文摘要	Pyrotinib is a novel irreversible tyrosine kinase inhibitor developed for the treatment of human epidermal growth factor receptor 2 (her2)-positive breast cancer. the results of phase i clinical trial demonstrated that pyrotinib was well tolerated and exhibited potent antitumor activity. as a promising therapeutic agent for her2-positive breast cancer, it is of great importance to investigate the biotransformation of pyrotinib in humans and identify the major enzymes involved in its metabolism during its early stage of development for safety consideration. for this purpose, a robust analytical method based on ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (uplc/q-tof ms) was established to characterize the metabolites of pyrotinib in human plasma, feces, and urine, and identify the primary enzymes responsible for its metabolism. as a result, a total of 24 metabolites were identified, including 16 phase i metabolites resulting from dealkylation, oxidation, dehydrogenation, and carbonylation, and 8 phase ii metabolites originating from cysteine and n-acetylcysteine conjugation. pyrotinib was absorbed into blood by 1 h, reached its peak level at 4 h, and afterwards underwent slow elimination. the principal metabolites detected in humans (m1, m2, and m5) were products resulting from o-depicoline and pyrrolidine lactam formation, whose structures have been confirmed by the synthetic references. in addition, fecal clearance was the major route of excretion for pyrotinib. further phenotyping experiment proved that cyp3a4 was the most active enzyme responsible for the biotransformation of pyrotinib, implying the vital necessity of the assessment of the potential cyp3a-mediated drug-drug interactions in humans. taken together, this study provided valuable metabolic data to explicate the dynamic process of pyrotinib in humans, and important reference basis for its safety evaluation and rational clinical application. the results will also benefit the assessment of the contributions to the overall activity or toxicity from the key metabolites. (c) 2016 elsevier b.v. all rights reserved.
WOS关键词	HER2-POSITIVE BREAST-CANCER ; TRASTUZUMAB RESISTANCE ; NERATINIB ; RECEPTOR ; IDENTIFICATION ; INHIBITORS ; BIOTRANSFORMATION ; PHARMACOKINETICS ; AFATINIB ; THERAPY
WOS研究方向	Biochemistry & Molecular Biology ; Chemistry
WOS类目	Biochemical Research Methods ; Chemistry, Analytical
语种	英语
出版者	ELSEVIER SCIENCE BV
WOS记录号	WOS:000385322600015
内容类型	期刊论文
URI标识	http://www.corc.org.cn/handle/1471x/2374870
专题	中国科学院大学
通讯作者	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.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Jiangsu Hengrui Med Co Ltd, Shanghai 200122, Peoples R China
推荐引用方式 GB/T 7714	Zhu, Yunting,Li, Liang,Zhang, Ge,et al. Metabolic characterization of pyrotinib in humans by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry[J]. Journal of chromatography b-analytical technologies in the biomedical and life sciences,2016,1033:117-127.
APA	Zhu, Yunting.,Li, Liang.,Zhang, Ge.,Wan, Hong.,Yang, Changyong.,...&Zhong, Dafang.(2016).Metabolic characterization of pyrotinib in humans by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry.Journal of chromatography b-analytical technologies in the biomedical and life sciences,1033,117-127.
MLA	Zhu, Yunting,et al."Metabolic characterization of pyrotinib in humans by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry".Journal of chromatography b-analytical technologies in the biomedical and life sciences 1033(2016):117-127.

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