Abstract
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.
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Acknowledgements
This work was partially supported by the National Natural Science Foundation of China (No 81521005), the Strategic Priority Research Program of the Chinese Academy of Sciences (No XDA12050306), the National Key New Drug Creation Special Programs (No 2017ZX09304-021), Jiangsu Provincial Medical Youth Talent (QNRC2016714), National Natural Science Foundation of China (No.81773820), the Jiangsu Provincial Medical Talent (ZDRCA2016048) and the Suzhou Key Laboratory of Drug Clinical Research and Personalized Medicine (SZS201719).
Author contribution
JM, XYC, DFZ, and LYM were responsible for study design and data analyses. JM, X-YL, SMA, HZ, SDY, YFZ, MXC, XYZ, YL, LY, and XLD conducted the study. YFZ conducted data analyses. JM and DFZ were responsible for writing the manuscript.
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Meng, J., Liu, Xy., Ma, S. et al. Metabolism and disposition of pyrotinib in healthy male volunteers: covalent binding with human plasma protein. Acta Pharmacol Sin 40, 980–988 (2019). https://doi.org/10.1038/s41401-018-0176-6
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DOI: https://doi.org/10.1038/s41401-018-0176-6
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