Metabolism and disposition of pyrotinib in healthy male volunteers: covalent binding with human plasma protein
Open accessAbstract
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 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 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 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.
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Pyrotinib covalently binds to ATP binding sites in intracellular kinase regions of EGFR, HER2 and HER4, preventing homodimer formation, thereby irreversibly inhibiting autophosphorylation, blocking activation of downstream signaling pathways, and inhibiting tumor cell growth.
“Similarly, as the third-generation EGFR TKI, pyrotinib covalently binds to ATP binding sites in intracellular kinase regions of EGFR, HER2 and HER4, preventing homodimer formation, thereby irreversibly inhibiting autophosphorylation, blocking activation of downstream signaling pathways, and inhibiting tumor cell growth.156–158”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [157]
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- Authors
- Meng, J., Liu, X.-Y., Ma, S., Zhang, H., Yu, S.-D., Zhang, Y.-F., Chen, M.-X., Zhu, X.-Y., Liu, Y., Yi, L., Ding, X.-L., Chen, X.-Y., Miao, L.-Y., & Zhong, D.-F.
- Affiliations
- Chinese Academy of Sciences (CN)
- Soochow University (CN)
- Jiangsu Hengrui Medicine (China) (CN)
- Corresponding author
- Miao, Li-yan
- Venue
- Acta Pharmacologica Sinica
- Published
- 2018-10-31
- Volume
- 40
- Issue
- 7
- Pages
- 980-988
- ISSN
- 0253-9756 (ISSN-L)
- 1671-4083
- 1745-7254
- PMC
- PMC6786348
- OpenAlex
- W2899115689
- Cited by
- 41
- References
- 23
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 2 · 2023: 9 · 2022: 6 · 2021: 8 · 2020: 6 · 2019: 1
- FWCI
- 4.13
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Acta Pharmacologica Sinica (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Agilent Technologies
- National Natural Science Foundation of China (2017ZX09304021, 81773820, No 81521005, 81521005)
- Chinese Academy of Sciences (XDA12050306)
- Jiangsu Provincial Medical Youth Talent (ZDRCA2016048, QNRC2016714)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- pyrotinib, drug metabolism, pharmacokinetics, covalent binding, human serum albumin, Michael addition, irreversible tyrosine kinase inhibitor, HER2-positive breast cancer, oxidative metabolites, plasma protein binding, fecal excretion
- MeSH terms
- Serum Albumin, Human, Acrylamides, Adult, Aminoquinolines, Antineoplastic Agents, Blood Chemical Analysis, Carbon Radioisotopes, Feces, Humans, Male, Orosomucoid, Protein Binding, Urine, Protein Kinase Inhibitors
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