19
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

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

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          Related collections

          Most cited references40

          • Record: found
          • Abstract: found
          • Article: not found

          Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance.

          The increased use of antibacterial and antifungal agents in recent years has resulted in the development of resistance to these drugs. The significant clinical implication of resistance has led to heightened interest in the study of antimicrobial resistance from different angles. Areas addressed include mechanisms underlying this resistance, improved methods to detect resistance when it occurs, alternate options for the treatment of infections caused by resistant organisms, and strategies to prevent and control the emergence and spread of resistance. In this review, the mode of action of antifungals and their mechanisms of resistance are discussed. Additionally, an attempt is made to discuss the correlation between fungal and bacterial resistance. Antifungals can be grouped into three classes based on their site of action: azoles, which inhibit the synthesis of ergosterol (the main fungal sterol); polyenes, which interact with fungal membrane sterols physicochemically; and 5-fluorocytosine, which inhibits macromolecular synthesis. Many different types of mechanisms contribute to the development of resistance to antifungals. These mechanisms include alteration in drug target, alteration in sterol biosynthesis, reduction in the intercellular concentration of target enzyme, and overexpression of the antifungal drug target. Although the comparison between the mechanisms of resistance to antifungals and antibacterials is necessarily limited by several factors defined in the review, a correlation between the two exists. For example, modification of enzymes which serve as targets for antimicrobial action and the involvement of membrane pumps in the extrusion of drugs are well characterized in both the eukaryotic and prokaryotic cells.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Current concepts in antifungal pharmacology.

            The introduction of new antifungal agents (eg, echinocandins, second-generation triazoles) in the past decade has transformed the management of invasive mycoses to the point that drug toxicity is no longer the major limiting factor in treatment. Yet, many of these newer antifungal agents have important limitations in their spectrum of activity, pharmacokinetics, and unique predisposition for pharmacokinetic drug-drug interactions and unusual toxicities associated with long-term use. This article reviews key pharmacological aspects of systemic antifungal agents as well as evolving strategies, such as pharmacokinetic-pharmacodynamic optimization and therapeutic drug monitoring, to improve the safety and efficacy of systemic antifungal therapy.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              LC-MS-based metabolomics in drug metabolism.

              Xenobiotic metabolism, a ubiquitous natural response to foreign compounds, elicits initiating signals for many pathophysiological events. Currently, most widely used techniques for identifying xenobiotic metabolites and metabolic pathways are empirical and largely based on in vitro incubation assays and in vivo radiotracing experiments. Recent work in our lab has shown that LC-MS-based metabolomic techniques are useful tools for xenobiotic metabolism research since multivariate data analysis in metabolomics can significantly rationalize the processes of xenobiotic metabolite identification and metabolic pathway analysis. In this review, the technological elements of LC-MS-based metabolomics for constructing high-quality datasets and conducting comprehensive data analysis are examined. Four novel approaches of using LC-MS-based metabolomic techniques in xenobiotic metabolism research are proposed and illustrated by case studies and proof-of-concept experiments, and the perspective on their application is further discussed.
                Bookmark

                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                13 March 2017
                March 2017
                : 18
                : 3
                : 621
                Affiliations
                [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; jhyunkim@ 123456catholic.ac.kr (J.-H.K.); cwg0222@ 123456catholic.ac.kr (W.-G.C.)
                [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; sangkyu@ 123456knu.ac.kr
                Author notes
                [* ]Correspondence: sianalee@ 123456catholic.ac.kr ; Tel.: +82-2-2164-4061; Fax: +82-32-342-2013
                Article
                ijms-18-00621
                10.3390/ijms18030621
                5372636
                28335386
                3ddb5f26-f1dd-48d6-ac5f-c00177c77186
                © 2017 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 19 February 2017
                : 09 March 2017
                Categories
                Article

                Molecular biology
                ketoconazole,metabolite profiling,bioactivation,metabolomics
                Molecular biology
                ketoconazole, metabolite profiling, bioactivation, metabolomics

                Comments

                Comment on this article