Metabolic profiles of ribociclib in rat and human liver microsomes using liquid chromatography combined with electrospray ionization high‐resolution mass spectrometry

Abstract

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, MS2 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.

Development and Validation of a Quantitative LC-MS/MS Method for CDK4/6 Inhibitors Palbociclib, Ribociclib, Abemaciclib, and Abemaciclib-M2 in Human Plasma

“…However, this limitation could be addressed by monitoring virtual parent-product ion transitions based on the expected fragmentation patterns of ribociclib and palbociclib. 23,24 This strategy will be applied to the ongoing pharmacogenetic study (BDR-122719).…”

Binimetinib Is a Potent Reversible and Time-Dependent Inhibitor of Cytochrome P450 1A2

“…Binimetinib includes a potential structural alert, para-phenylenediamine that is prone to CYPs-mediated oxidation, resulting in the formation of 1,4-diiminoquinone. 16,17 This intermediate is chemically reactive to a nucleophilic agent like GSH. In the current study, 1,4-diiminoquinone was hypothesized to be the reactive metabolite responsible for protein modification, and GSH was used as a nucleophile to trap this intermediate.…”