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

Jian Meng1, Xiao-yun Liu1, Sheng Ma2,3, Hua Zhang2,3, Song-da Yu1, Yi-fan Zhang1, Mei-xia Chen4, Xiao-yu Zhu4, Yi Liu4, Ling Yi2,3, Xiao-liang Ding2,3, Xiao-yan Chen1, Li-yan Miao2,3, Da-fang Zhong1
1 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201210, China
2 The First Affiliated Hospital of Soochow University, Suzhou 215006, China
3 Institute for Interdisciplinary Drug Research and Translational Sciences, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
4 Jiangsu Hengrui Medicine Co., Ltd, Lianyungang 222047, China
Correspondence to: Li-yan Miao:, Da-fang Zhong:,
DOI: 10.1038/s41401-018-0176-6
Received: 11 June 2018
Accepted: 24 September 2018
Advance online: 31 October 2018


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 [14C]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 AUC0–∞ ratios. Approximately 58.3% of the total plasma radioactivity AUC0–∞ was attributed to covalently bound materials. After incubation of human plasma with [14C]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.
Keywords: pyrotinib; EGFR/HER2 dual tyrosine kinase inhibitor; breast cancer; drug metabolism; drug disposition; human plasma; covalent binding

Article Options

Download Citation

Cited times in Scopus