LC-MS/MS reveals the formation of aldehydes and iminium reactive intermediates in foretinib metabolism: phase I metabolic profiling
Foretinib (GSK1363089) is an inhibitor of multiple receptor tyrosine kinases including MET and VEGFR, with the potential for treatment of solid tumors. In this study, we investigated the in vitro metabolic pathways for foretinib in rat liver microsomes using LC-MS/MS. Methoxylamine and potassium cya...
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Published in | RSC advances Vol. 7; no. 58; pp. 36279 - 36287 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
01.01.2017
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Online Access | Get full text |
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Summary: | Foretinib (GSK1363089) is an inhibitor of multiple receptor tyrosine kinases including MET and VEGFR, with the potential for treatment of solid tumors. In this study, we investigated the
in vitro
metabolic pathways for foretinib in rat liver microsomes using LC-MS/MS. Methoxylamine and potassium cyanide were used as trapping agents for aldehyde and iminium reactive intermediates, respectively, of foretinib to form a stable complex that can be identified by LC-MS/MS. Six foretinib phase I metabolites were characterized. The phase I metabolic pathways were oxidation, defluorination, reduction and hydroxylation. Additionally, four potential reactive metabolites, two aldehydes and two iminium ions, were found and the bioactivation pathways were proposed. Reporting the
in vitro
and reactive metabolites of foretinib is very crucial in the development stage. A literature review showed that no previous articles have provided an
in vitro
metabolism study of foretinib or detailed structural identification of the formed reactive metabolites.
Using LC-MS/MS, six phase I foretinib metabolites in addition to four potential reactive metabolites, two aldehydes and two iminium ions, were detected and the bioactivation pathways were proposed. |
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ISSN: | 2046-2069 2046-2069 |
DOI: | 10.1039/c7ra06341e |