Detection and characterization of olmutinib reactive metabolites by LC–MS/MS: Elucidation of bioactivation pathways
Abstract
Olmutinib (Olita™) is an orally bioavailable third generation epidermal growth factor receptor tyrosine kinase inhibitor. Olmutinib was approved in South Korea in May 2016 for the treatment of patients suffering from locally advanced or metastatic epidermal growth factor receptor T790M mutation‐positive non‐small cell lung cancer. Reactive olmutinib intermediates may be responsible for the severe side effects associated with the treatment. However, literature review revealed no previous reports on the structural identification of reactive olmutinib metabolites. In this work, the formation of reactive olmutinib metabolites in rat liver microsomes was investigated. Methoxylamine, glutathione, and potassium cyanide were used as capturing agents for aldehyde, iminoquinones, and iminium intermediates, respectively. The stable complexes formed were identified using liquid chromatography–tandem mass spectrometry. The major phase I metabolic pathway observed in vitro was hydroxylation of the piperazine ring. Seven potential reactive intermediates were characterized, including three iminium ions, three iminoquinones, and one aldehyde. Based on the findings, various bioactivation pathways were postulated. Hence, identifying the reactive intermediates of olmutinib that may be the cause of severe side effects can provide new insights, leading to improved treatments for patients.
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Olmutinib binds to cysteine residues near the kinase domain, thereby inducing cell death in tumor cells expressing EGFR.
“It binds to cysteine residues near the kinase domain, thereby inducing cell death in tumor cells expressing EGFR.152,153”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [153]
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works
- Authors
- Attwa, M. W., Kadi, A. A., & Abdelhameed, A. S.
- Affiliations
- Mansoura University (EG)
- King Saud University (SA)
- Corresponding author
- Abdelhameed, Ali S.
- Venue
- Journal of Separation Science
- Publisher
- Wiley
- Published
- 2019-12-02
- Volume
- 43
- Issue
- 4
- Pages
- 708-718
- ISSN
- 1615-9306 (ISSN-L)
- 1615-9314
- OpenAlex
- W2984767608
- Cited by
- 37
- References
- 48
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 6 · 2022: 5 · 2021: 12 · 2020: 9
- FWCI
- 6.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Separation Science (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Physical Sciences › Chemistry › Analytical Chemistry › Analytical Methods in Pharmaceuticals
- Keywords
- reactive metabolites, epidermal growth factor receptor tyrosine kinase inhibitors, iminium intermediates, iminoquinone, aldehyde intermediates, glutathione adducts, adverse drug reactions, non-small cell lung cancer, T790M mutation, rat liver microsomes
- MeSH terms
- Animals, Antineoplastic Agents, Chromatography, High Pressure Liquid, Humans, Microsomes, Liver, Piperazines, Pyrimidines, Molecular Structure, Protein Kinase Inhibitors, Rats, Tandem Mass Spectrometry
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