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Int. J. Mol. Sci. 2017, 18(3), 621; doi:10.3390/ijms18030621

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

1
Drug Metabolism and Bioanalysis Laboratory, College of Pharmacy, The Catholic University of Korea, 43 Jibong-ro, Wonmi-gu, Bucheon-si, Gyeonggi-do 14662, Korea
2
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
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)
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Abstract

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
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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.

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