Metabolic characterization of pyrotinib in humans by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry
文献类型：期刊论文
| 作者 | Zhu, Yunting1,2; Li, Liang1 ; Zhang, Ge3; Wan, Hong3; Yang, Changyong3; Diao, Xingxing1; Chen, Xiaoyan1; Zhang, Lianshan3; Zhong, Dafang1
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| 刊名 | JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
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| 出版日期 | 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 |
| 文献子类 | Article |
| 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 |
| 资助项目 | National Natural Science Foundation of China[81521005] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000385322600015 |
| 出版者 | ELSEVIER SCIENCE BV |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/275855]  |
| 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 | 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. |
入库方式： OAI收割
来源：上海药物研究所
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