metabolismanddispositionofpyrotinibinhealthymalevolunteerscovalentbindingwithhumanplasmaprotein

doi:10.1038/s41401-018-0176-6

	metabolismanddispositionofpyrotinibinhealthymalevolunteerscovalentbindingwithhumanplasmaprotein
	Meng Jian 1; Liu Xiaoyun 1; Ma Sheng 2; Zhang Hua 2; Yu Songda 1; Zhang Yifan 1; Chen Meixia 3; Zhu Xiaoyu 3; Liu Yi 3; Yi Ling 2
刊名	actapharmacologicasinica
	2019
卷号	40 期号:7 页码:980
关键词	pyrotinib EGFR/HER2 dual tyrosine kinase inhibitor breast cancer drug metabolism drug disposition human plasma covalent binding
ISSN号	1671-4083
DOI	10.1038/s41401-018-0176-6
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 (14)Cpyrotinib. 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_(0-∞) ratios. Approximately 58.3% of the total plasma radioactivity AUC_(0-∞) was attributed to covalently bound materials. After incubation of human plasma with ~(14)Cpyrotinib 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/2S10ELR8/284833]
专题	中国科学院上海药物研究所
作者单位	1.中国科学院上海药物研究所 2.苏州大学 3.Jiangsu Hengrui Medicine Co., Ltd
推荐引用方式 GB/T 7714	Meng Jian,Liu Xiaoyun,Ma Sheng,et al. metabolismanddispositionofpyrotinibinhealthymalevolunteerscovalentbindingwithhumanplasmaprotein[J]. actapharmacologicasinica,2019,40(7):980.
APA	Meng Jian.,Liu Xiaoyun.,Ma Sheng.,Zhang Hua.,Yu Songda.,...&Zhong Dafang.(2019).metabolismanddispositionofpyrotinibinhealthymalevolunteerscovalentbindingwithhumanplasmaprotein.actapharmacologicasinica,40(7),980.
MLA	Meng Jian,et al."metabolismanddispositionofpyrotinibinhealthymalevolunteerscovalentbindingwithhumanplasmaprotein".actapharmacologicasinica 40.7(2019):980.