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- Title
Detection and characterization of olmutinib reactive metabolites by LC–MS/MS: Elucidation of bioactivation pathways.
- Authors
Attwa, Mohamed W.; Kadi, Adnan A.; Abdelhameed, Ali S.
- 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.
- Subjects
SOUTH Korea; EPIDERMAL growth factor receptors; LIQUID chromatography-mass spectrometry; METABOLITES; NON-small-cell lung carcinoma; POTASSIUM cyanide; DASATINIB; PEMETREXED
- Publication
Journal of Separation Science, 2020, Vol 43, Issue 4, p708
- ISSN
1615-9306
- Publication type
Article
- DOI
10.1002/jssc.201900818