NDLI: Detection and characterization of ponatinib reactive metabolites by liquid chromatography tandem mass spectrometry and elucidation of bioactivation pathways

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Detection and characterization of ponatinib reactive metabolites by liquid chromatography tandem mass spectrometry and elucidation of bioactivation pathways

Content Provider	Semantic Scholar
Author	Kadi, Adnan A. Darwish, Hany W. Attwa, Mohamed W. Amer, Sawsan Mohamed
Copyright Year	2016
Abstract	Ponatinib (PNT), as a multi-targeted tyrosine kinase inhibitor, is active against T315I and other BCR-ABL mutants. PNT is registered in the U.S. and EU under the trade name of Iclusig®. The current study reports the identification and characterization of in vitro metabolites of PNT, which were produced by its incubation with rat liver microsomes (RLMs). PNT and its metabolites were extracted from the incubation mixture by the protein precipitation procedure and the supernatants were injected into high performance liquid chromatography tandem mass spectrometry (LC-MS/MS) equipment. Reversed phase liquid chromatography resolved seven in vitro PNT metabolites. Each metabolite displayed one or more metabolic reaction pathways including N-demethylation, N-oxide formation, oxidation, reduction and hydroxylation. Structures of the PNT metabolites showed high liability to form reactive metabolites. Since bioactivation is often speculated to be responsible for observed idiosyncratic toxicities including hepatotoxicity, incubation of PNT with RLMs was carried out in the presence of 1.0 mM GSH or 1.0 mM KCN to check its reactive metabolites. No GSH adduct was found while four cyano adduct metabolites were determined and their structures were proposed based on the mass scan and product ion data for each metabolite.
Starting Page	72575
Ending Page	72585
Page Count	11
File Format	PDF HTM / HTML
DOI	10.1039/C6RA09985H
Alternate Webpage(s)	http://pubs.rsc.org/en/content/articlepdf/2017/ra/c7ra90020a
Alternate Webpage(s)	https://pubs.rsc.org/en/content/articlepdf/2017/ra/c7ra90020a
Alternate Webpage(s)	https://doi.org/10.1039/C6RA09985H
Volume Number	6
Language	English
Access Restriction	Open
Content Type	Text
Resource Type	Article

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