Premium
In vitro metabolism of ibrutinib in rat, dog and human hepatocytes using liquid chromatography combined with diode‐array detection and Q‐Exactive Orbitrap tandem mass spectrometry
Author(s) -
Dong Jiangnan,
Li Su,
Liu Guangxuan
Publication year - 2019
Publication title -
rapid communications in mass spectrometry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.528
H-Index - 136
eISSN - 1097-0231
pISSN - 0951-4198
DOI - 10.1002/rcm.8542
Subject(s) - chemistry , ibrutinib , hydroxylation , mass spectrometry , orbitrap , chromatography , tandem mass spectrometry , biochemistry , enzyme , leukemia , medicine , chronic lymphocytic leukemia
Rationale Ibrutinib is a potent Bruton's tyrosine kinase inhibitor which has shown promising efficacy against various B‐cell malignancies. Its metabolic profiles have not been disclosed. The aim of this study was to investigate the metabolism of ibrutinib in the hepatocytes of rat, dog and human. Methods Ibrutinib was incubated with hepatocytes at 37°C for 2 h, after which the samples were analyzed using ultrahigh‐performance liquid chromatography with diode‐array detection and Q‐Exactive Orbitrap tandem mass spectrometry (UHPLC/DAD‐Q‐Exactive‐Orbitrap‐MS). The acquired data were processed using MetWorks™ software. Results A total of 20 metabolites were structurally identified by their MS and MS 2 data. M1 and M5 were unambiguously identified using authentic standards. The biotransformation of ibrutinib involved hydroxylation, hydration, oxygenation, epoxide hydrolysis, dehydrogenation, dealkylation and GSH conjugation. Conclusions Humans have a relatively low capability for metabolizing ibrutinib. Compared with rat, dog had closer metabolic profiles to humans and would be more suitable for toxicity studies. This study provides more valuable information with respect to the in vitro disposition of ibrutinib.