Metabolism and disposition of pyrotinib in healthy male volunteers: covalent binding with human plasma protein

doi:10.1038/s41401-018-0176-6

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 上海药物代谢研究中心

	Metabolism and disposition of pyrotinib in healthy male volunteers: covalent binding with human plasma protein
	Meng, Jian3 ; Liu, Xiao-Yun 3; Ma, Sheng 2; Zhang, Hua 2; Yu, Song-da 3; Zhang, Yi-Fan3 ; Chen, Mei-Xia 1; Zhu, Xiao-Yu 1; Liu, Yi 1; Yi, Ling 2
刊名	Acta pharmacologica Sinica
	2018-10-31
ISSN号	1745-7254
DOI	10.1038/s41401-018-0176-6
文献子类	Article
英文摘要	Pyrotinib is a novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor that is used to treat HER2-positive breast cancer. In this study we investigated the metabolism and disposition of pyrotinib in six healthy Chinese men after a single oral dose of 402 mg of [C]pyrotinib. At 240 h postdose, the mean cumulative excretion of the dose radioactivity was 92.6%, including 1.7% in urine and 90.9% in feces. In feces, oxidative metabolites were detected as major drug-related materials and the primary metabolic pathways were O-depicoline (M1), oxidation of pyrrolidine (M5), and oxidation of pyridine (M6-1, M6-2, M6-3, and M6-4). In plasma, the major circulating entities identified were pyrotinib, SHR150980 (M1), SHR151468 (M2), and SHR151136 (M5), accounting for 10.9, 1.9, 1.0, and 3.0%, respectively, of the total plasma radioactivity based on the AUC ratios. Approximately 58.3% of the total plasma radioactivity AUC was attributed to covalently bound materials. After incubation of human plasma with [C]pyrotinib at 37 °C for 2, 5, 8, and 24 h, the recovery of radioactivity by extraction was 97.4, 91.8, 69.6, and 46.7%, respectively, revealing covalent binding occurred independently of enzymes. A group of pyrotinib adducts, including pyrotinib-lysine and pyrotinib adducts of the peptides Gly-Lys, Lys-Ala, Gly-Lys-Ala, and Lys-Ala-Ser, was identified after HCl hydrolysis of the incubated plasma. Therefore, the amino acid residue Lys190 of human serum albumin was proposed to covalently bind to pyrotinib via Michael addition. Finally, the covalently bound pyrotinib could dissociate from the human plasma protein and be metabolized by oxidation and excreted via feces.
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/266629]
专题	上海药物代谢研究中心
通讯作者	Miao, Li-Yan; Zhong, Da-Fang
作者单位	1.Jiangsu Hengrui Medicine Co., Ltd, Lianyungang, 222047, China 2.The First Affiliated Hospital of Soochow University, Suzhou, 215006, China; 3.Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201210, China;
推荐引用方式 GB/T 7714	Meng, Jian,Liu, Xiao-Yun,Ma, Sheng,et al. Metabolism and disposition of pyrotinib in healthy male volunteers: covalent binding with human plasma protein[J]. Acta pharmacologica Sinica,2018.
APA	Meng, Jian.,Liu, Xiao-Yun.,Ma, Sheng.,Zhang, Hua.,Yu, Song-da.,...&Zhong, Da-Fang.(2018).Metabolism and disposition of pyrotinib in healthy male volunteers: covalent binding with human plasma protein.Acta pharmacologica Sinica.
MLA	Meng, Jian,et al."Metabolism and disposition of pyrotinib in healthy male volunteers: covalent binding with human plasma protein".Acta pharmacologica Sinica (2018).