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

被引:35
作者
Kadi, Adnan A. [1 ]
Darwish, Hany W. [1 ]
Attwa, Mohamed W. [1 ,2 ]
Amer, Sawsan M. [1 ]
机构
[1] King Saud Univ, Coll Pharm, Dept Pharmaceut Chem, POB 2457, Riyadh 11451, Saudi Arabia
[2] Cairo Univ, Analyt Chem Dept, Fac Pharm, Kasr El Aini St, Cairo 11562, Egypt
关键词
TYROSINE KINASE INHIBITORS; IMINIUM; CANCER; MICROSOMES; RESISTANCE;
D O I
10.1039/c6ra09985h
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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 (R). 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.
引用
收藏
页码:72575 / 72585
页数:11
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