Premium
Metabolic profiles of ribociclib in rat and human liver microsomes using liquid chromatography combined with electrospray ionization high‐resolution mass spectrometry
Author(s) -
Liu Na,
Liu Hongqiang,
Zhang Wucheng,
Yao Huijie
Publication year - 2020
Publication title -
biomedical chromatography
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.4
H-Index - 65
eISSN - 1099-0801
pISSN - 0269-3879
DOI - 10.1002/bmc.4783
Subject(s) - chemistry , microsome , chromatography , mass spectrometry , electrospray ionization , glutathione , metabolic pathway , drug metabolism , adduct , metabolite , electrospray , metabolism , biochemistry , in vitro , enzyme , organic chemistry
Ribociclib is a highly specific CDK4/6 inhibitor. Determination of the metabolism of ribociclib is required during the drug development stage. In this study, metabolic profiles of ribociclib were investigated using rat and human liver microsomes. Metabolites were structurally identified by liquid chromatography electrospray ionization high‐resolution mass spectrometry operated in positive‐ion mode. The metabolites were characterized by accurate masses, MS 2 spectra and retention times. With rat and human liver microsomes, a total of 10 metabolites were detected and further identified. No human‐specific metabolites were detected. The metabolic pathways of ribociclib were oxygenation, demethylation and dealkylation. Most importantly, two glutathione (GSH) adducts were identified in human liver microsomes fortified with GSH. The formation of the GSH adducts was hypothesized to be through the oxidation of electron‐rich 1,4‐benzenediamine to a 1,4‐diiminoquinone intermediate, which is highly reactive and can be trapped by GSH to form stable metabolites. The current study provides an overview of the metabolic profiles of ribociclib in vitro , which will be of great help in understanding the efficacy and toxicity of this drug.