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      Models of Drug Induced Liver Injury (DILI) – Current Issues and Future Perspectives

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          Abstract

          Background:

          Drug-induced Liver Injury (DILI) is an important cause of acute liver failure cases in the United States, and remains a common cause of withdrawal of drugs in both preclinical and clinical phases.

          Methods:

          A structured search of bibliographic databases – Web of Science Core Collection, Scopus and Medline for peer-reviewed articles on models of DILI was performed. The reference lists of relevant studies was prepared and a citation search for the included studies was carried out. In addition, the characteristics of screened studies were described.

          Results:

          One hundred and six articles about the existing knowledge of appropriate models to study DILI in vitro and in vivo with special focus on hepatic cell models, variations of 3D co-cultures, animal models, databases and predictive modeling and translational biomarkers developed to understand the mechanisms and pathophysiology of DILI are described.

          Conclusion:

          Besides descriptions of current applications of existing modeling systems, associated advantages and limitations of each modeling system and future directions for research development are discussed as well.

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          Most cited references85

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          The current state of serum biomarkers of hepatotoxicity.

          The level of serum alanine aminotransferase (ALT) activity reflects damage to hepatocytes and is considered to be a highly sensitive and fairly specific preclinical and clinical biomarker of hepatotoxicity. However, an increase in serum ALT activity level has also been associated with other organ toxicities, thus, indicating that the enzyme has specificity beyond liver in the absence of correlative histomorphologic alteration in liver. Thus, unidentified non-hepatic sources of serum ALT activity may inadvertently influence the decision of whether to continue development of a novel pharmaceutical compound. To assess the risk of false positives due to extraneous sources of serum ALT activity, additional biomarkers are sought with improved specificity for liver function compared to serum ALT activity alone. Current published biomarker candidates are reviewed herein and compared with ALT performance in preclinical and on occasion, clinical studies. An examination of the current state of hepatotoxic biomarkers indicates that serum F protein, arginase I, and glutathione-S-transferase alpha (GSTalpha) levels, all measured by ELISA, may show utility, however, antibody availability and high cost per run may present limitations to widespread applicability in preclinical safety studies. In contrast, the enzymatic markers sorbitol dehydrogenase, glutamate dehydrogenase, paraxonase, malate dehydrogenase, and purine nucleoside phosphorylase are all readily measured by photometric methods and use reagents that work across preclinical species and humans and are commercially available. The published literature suggests that these markers, once examined collectively in a large qualification study, could provide additional information relative to serum ALT and aspartate aminotransferase (AST) values. Since these biomarkers are found in the serum/plasma of treated humans and rats, they have potential to be utilized as bridging markers to monitor acute drug-induced liver injury in early clinical trials.
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            Drug-induced hepatotoxicity.

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              Idiosyncratic drug hepatotoxicity.

              The occurrence of idiosyncratic drug hepatotoxicity is a major problem in all phases of clinical drug development and the most frequent cause of post-marketing warnings and withdrawals. This review examines the clinical signatures of this problem, signals predictive of its occurrence (particularly of more frequent, reversible, low-grade injury) and the role of monitoring in prevention by examining several recent examples (for example, troglitazone). In addition, the failure of preclinical toxicology to predict idiosyncratic reactions, and what can be done to improve this problem, is discussed. Finally, our current understanding of the pathophysiology of experimental drug hepatotoxicity is examined, focusing on acetaminophen, particularly with respect to the role of the innate immune system and control of cell-death pathways, which might provide targets for exploration and identification of risk factors and mechanisms in humans.
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                Author and article information

                Journal
                Curr Drug Metab
                Curr. Drug Metab
                CDM
                Current Drug Metabolism
                Bentham Science Publishers
                1389-2002
                1875-5453
                August 2018
                August 2018
                : 19
                : 10
                : 830-838
                Affiliations
                Department of Pharmacology, Faculty of Medicine, J. J. Strossmayer University of Osijek, J. Huttlera 4, 31000, Osijek , Croatia; Department of Pharmacology, Faculty Of Dental Medicine and Health, J. J. Strossmayer University of Osijek, Crkvena 21, 31000, Osijek , Croatia; Department of Chemistry and Biochemistry, Faculty of Dental Medicine and Health, J. J. Strossmayer University of Osijek, Crkvena 21, 31000, Osijek , Croatia; Inspecto, LLC, Martina Divalta 193, 31000, Osijek , Croatia; Department of Medicine, Division of Gastroenterology-Hepatology, University of Connecticut Health Center , Farmington, , CT , USA
                Author notes
                [* ]Address correspondence to this author at the J. J. Strossmayer University of Osijek, Faculty of Medicine Osijek, Department of Pharmacology, J. Huttlera 4, 31 000 Osijek, Croatia; Tel: + 0385-31-512-800; Fax: +385-31-512-833; E-mail: martina.smolic@ 123456mefos.hr
                [§: ]

                Both authors contributed equally to this work.

                Article
                CDM-19-830
                10.2174/1389200219666180523095355
                6174638
                29788883
                213c7f4b-77e6-4f07-92d7-a927f21418ca
                © 2018 Bentham Science Publishers

                This is an open access article licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) ( https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

                History
                : 09 January 2018
                : 20 March 2018
                : 28 March 2018
                Categories
                Article

                Pharmacology & Pharmaceutical medicine
                drug evaluation studies,preclinical,evidence-based toxicology,liver injury,drug-induced,side effects

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