Next Article in Journal
Dectin-1-Mediated Pathway Contributes to Fusarium proliferatum-Induced CXCL-8 Release from Human Respiratory Epithelial Cells
Next Article in Special Issue
In Silico and In Vitro Analysis of Interaction between Ximelagatran and Human Leukocyte Antigen (HLA)-DRB1*07:01
Previous Article in Journal
A Biomedical Investigation of the Hepatoprotective Effect of Radix salviae miltiorrhizae and Network Pharmacology-Based Prediction of the Active Compounds and Molecular Targets
Previous Article in Special Issue
A New Oleanolic Acid Derivative against CCl4-Induced Hepatic Fibrosis in Rats
Open AccessArticle

Revisiting the Metabolism and Bioactivation of Ketoconazole in Human and Mouse Using Liquid Chromatography–Mass Spectrometry-Based Metabolomics

Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 14662, Korea
BK21 Plus KNU Multi-Omics based Creative Drug Research Team, College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea
Author to whom correspondence should be addressed.
Academic Editors: Rolf Teschke and Gaby Danan
Int. J. Mol. Sci. 2017, 18(3), 621;
Received: 19 February 2017 / Revised: 9 March 2017 / Accepted: 9 March 2017 / Published: 13 March 2017
(This article belongs to the Special Issue Molecular Research on Drug Induced Liver Injury)
Although ketoconazole (KCZ) has been used worldwide for 30 years, its metabolic characteristics are poorly described. Moreover, the hepatotoxicity of KCZ limits its therapeutic use. In this study, we used liquid chromatography–mass spectrometry-based metabolomics to evaluate the metabolic profile of KCZ in mouse and human and identify the mechanisms underlying its hepatotoxicity. A total of 28 metabolites of KCZ, 11 of which were novel, were identified in this study. Newly identified metabolites were classified into three categories according to the metabolic positions of a piperazine ring, imidazole ring, and N-acetyl moiety. The metabolic characteristics of KCZ in human were comparable to those in mouse. Moreover, three cyanide adducts of KCZ were identified in mouse and human liver microsomal incubates as “flags” to trigger additional toxicity study. The oxidation of piperazine into iminium ion is suggested as a biotransformation responsible for bioactivation. In summary, the metabolic characteristics of KCZ, including reactive metabolites, were comprehensively understood using a metabolomics approach. View Full-Text
Keywords: ketoconazole; metabolite profiling; bioactivation; metabolomics ketoconazole; metabolite profiling; bioactivation; metabolomics
Show Figures

Graphical abstract

MDPI and ACS Style

Kim, J.-H.; Choi, W.-G.; Lee, S.; Lee, H.S. Revisiting the Metabolism and Bioactivation of Ketoconazole in Human and Mouse Using Liquid Chromatography–Mass Spectrometry-Based Metabolomics. Int. J. Mol. Sci. 2017, 18, 621.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

Search more from Scilit
Back to TopTop