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      A Physiology-Based Model of Human Bile Acid Metabolism for Predicting Bile Acid Tissue Levels After Drug Administration in Healthy Subjects and BRIC Type 2 Patients

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          Abstract

          Drug-induced liver injury (DILI) is a matter of concern in the course of drug development and patient safety, often leading to discontinuation of drug-development programs or early withdrawal of drugs from market. Hepatocellular toxicity or impairment of bile acid (BA) metabolism, known as cholestasis, are the two clinical forms of DILI. Whole-body physiology-based modelling allows a mechanistic investigation of the physiological processes leading to cholestasis in man. Objectives of the present study were: (1) the development of a physiology-based model of the human BA metabolism, (2) population-based model validation and characterisation, and (3) the prediction and quantification of altered BA levels in special genotype subgroups and after drug administration. The developed physiology-based bile acid (PBBA) model describes the systemic BA circulation in humans and includes mechanistically relevant active and passive processes such as the hepatic synthesis, gallbladder emptying, transition through the gastrointestinal tract, reabsorption into the liver, distribution within the whole body, and excretion via urine and faeces. The kinetics of active processes were determined for the exemplary BA glycochenodeoxycholic acid (GCDCA) based on blood plasma concentration-time profiles. The robustness of our PBBA model was verified with population simulations of healthy individuals. In addition to plasma levels, the possibility to estimate BA concentrations in relevant tissues like the intracellular space of the liver enhance the mechanistic understanding of cholestasis. We analysed BA levels in various tissues of Benign Recurrent Intrahepatic Cholestasis type 2 (BRIC2) patients and our simulations suggest a higher susceptibility of BRIC2 patients toward cholestatic DILI due to BA accumulation in the liver. The effect of drugs on systemic BA levels were simulated for cyclosporine A (CsA). Our results confirmed the higher risk of DILI after CsA administration in healthy and BRIC2 patients. The presented PBBA model enhances our mechanistic understanding underlying cholestasis and drug-induced alterations of BA levels in blood and organs. The developed PBBA model might be applied in the future to anticipate potential risk of cholestasis in patients.

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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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            Drug-induced liver injury: recent advances in diagnosis and risk assessment

            Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially severe adverse drug reaction that should be considered in patients who develop laboratory criteria for liver injury secondary to the administration of a potentially hepatotoxic drug. Although currently used liver parameters are sensitive in detecting DILI, they are neither specific nor able to predict the patient's subsequent clinical course. Genetic risk assessment is useful mainly due to its high negative predictive value, with several human leucocyte antigen alleles being associated with DILI. New emerging biomarkers which could be useful in assessing DILI include total keratin18 (K18) and caspase-cleaved keratin18 (ccK18), macrophage colony-stimulating factor receptor 1, high mobility group box 1 and microRNA-122. From the numerous in vitro test systems that are available, monocyte-derived hepatocytes generated from patients with DILI show promise in identifying the DILI-causing agent from among a panel of coprescribed drugs. Several computer-based algorithms are available that rely on cumulative scores of known risk factors such as the administered dose or potential liabilities such as mitochondrial toxicity, inhibition of the bile salt export pump or the formation of reactive metabolites. A novel DILI cluster score is being developed which predicts DILI from multiple complimentary cluster and classification models using absorption–distribution–metabolism–elimination-related as well as physicochemical properties, diverse substructural descriptors and known structural liabilities. The provision of more advanced scientific and regulatory guidance for liver safety assessment will depend on validating the new diagnostic markers in the ongoing DILI registries, biobanks and public–private partnerships.
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              Organ/body-on-a-chip based on microfluidic technology for drug discovery

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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                27 September 2019
                2019
                : 10
                : 1192
                Affiliations
                [1] 1Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University , Aachen, Germany
                [2] 2Department of Surgery, University Hospital Aachen , Aachen, Germany
                [3] 3Unit of Experimental Hepatology, IIS Hospital La Fe, Faculty of Medicine, University of Valencia and CIBEREHD , Valencia, Spain
                Author notes

                Edited by: Doron Levy, University of Maryland, College Park, United States

                Reviewed by: Kalyan C. Vinnakota, Biotechnology HPC Software Applications Institute (BHSAI), United States; Alexey Goltsov, Abertay University, United Kingdom

                *Correspondence: Lars Kuepfer, lars.kuepfer@ 123456rwth-aachen.de

                This article was submitted to Systems Biology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2019.01192
                6777137
                31611804
                42715ac8-3495-431f-a644-66e4ff9912ff
                Copyright © 2019 Baier, Cordes, Thiel, Castell, Neumann, Blank and Kuepfer.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 18 February 2019
                : 03 September 2019
                Page count
                Figures: 6, Tables: 5, Equations: 5, References: 79, Pages: 13, Words: 0
                Categories
                Physiology
                Original Research

                Anatomy & Physiology
                pbpk,computational modelling,dili,bile acids,bric type 2,cholestasis
                Anatomy & Physiology
                pbpk, computational modelling, dili, bile acids, bric type 2, cholestasis

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