Permeabilized cryopreserved human hepatocytes as an exogenous metabolic system in a novelmetabolism-dependent cytotoxicity assay (MDCA) for the evaluation of metabolic activation anddetoxification of drugs associated with drug induced liver injuries: Results with acetaminophen,amiodarone, cyclophosphamide, ketoconazole, nefazodone, and troglitazone

2021 ◽  
pp. DMD-AR-2021-000645
Author(s):  
Hong Wei ◽  
Albert P. Li
Keyword(s):  
Metabolic Activation ◽  
Human Hepatocytes ◽  
Cytotoxicity Assay ◽  
Drug Induced ◽  
Metabolic System ◽  
Liver Injuries

scholarly journals Immune-Mediated Drug-Induced Liver Injury: Immunogenetics and Experimental Models

2021 ◽  
Vol 22 (9) ◽  
pp. 4557
Author(s):  
Alessio Gerussi ◽  
Ambra Natalini ◽  
Fabrizio Antonangeli ◽  
Clara Mancuso ◽  
Elisa Agostinetto ◽  
...  
Keyword(s):  
Liver Injury ◽  
Experimental Models ◽  
Clinical Event ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Immune Mediated ◽  
Liver Injuries ◽  
Immunological Mechanisms ◽  
Molecular Aspects ◽  
Therapeutic Tools

Drug-induced liver injury (DILI) is a challenging clinical event in medicine, particularly because of its ability to present with a variety of phenotypes including that of autoimmune hepatitis or other immune mediated liver injuries. Limited diagnostic and therapeutic tools are available, mostly because its pathogenesis has remained poorly understood for decades. The recent scientific and technological advancements in genomics and immunology are paving the way for a better understanding of the molecular aspects of DILI. This review provides an updated overview of the genetic predisposition and immunological mechanisms behind the pathogenesis of DILI and presents the state-of-the-art experimental models to study DILI at the pre-clinical level.

Metabolic activation in drug-induced liver injury

2012 ◽  
Vol 44 (1) ◽  
pp. 18-33 ◽  
Author(s):  
Louis Leung ◽  
Amit S. Kalgutkar ◽  
R. Scott Obach
Keyword(s):  
Liver Injury ◽  
Metabolic Activation ◽  
Drug Induced ◽  
Drug Induced Liver Injury

scholarly journals Characterisation of the NRF2 transcriptional network and its response to chemical insult in primary human hepatocytes: implications for prediction of drug-induced liver injury

2018 ◽  
Vol 93 (2) ◽  
pp. 385-399 ◽  
Author(s):  
Ian M. Copple ◽  
Wouter den Hollander ◽  
Giulia Callegaro ◽  
Fiona E. Mutter ◽  
James L. Maggs ◽  
...  
Keyword(s):  
Liver Injury ◽  
Transcriptional Network ◽  
Human Hepatocytes ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Primary Human Hepatocytes

scholarly journals Integrated ‘omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes

2018 ◽  
Vol 289 ◽  
pp. 1-13 ◽  
Author(s):  
Jarno E.J. Wolters ◽  
Simone G.J. van Breda ◽  
Jonas Grossmann ◽  
Claudia Fortes ◽  
Florian Caiment ◽  
...  
Keyword(s):  
Human Hepatocytes ◽  
Drug Induced ◽  
New Drug ◽  
Omics Analysis ◽  
Integrated Omics

Clinical recommendations: drug-induced liver injuries in adults

Therapy ◽  
2020 ◽  
Vol 4_2020 ◽  
pp. 52-76
Keyword(s):  
Drug Induced ◽  
Clinical Recommendations ◽  
Liver Injuries

Evaluation of transcriptomic signature as a valuable tool to study drug-induced cholestasis in primary human hepatocytes

2017 ◽  
Vol 91 (8) ◽  
pp. 2879-2893 ◽  
Author(s):  
Céline Parmentier ◽  
Philippe Couttet ◽  
Armin Wolf ◽  
Thomas Zaccharias ◽  
Bruno Heyd ◽  
...  
Keyword(s):  
Study Drug ◽  
Human Hepatocytes ◽  
Drug Induced ◽  
Primary Human Hepatocytes ◽  
Transcriptomic Signature

Metabolic activation and drug-induced liver injury:in vitroapproaches for the safety risk assessment of new drugs

2015 ◽  
Vol 36 (6) ◽  
pp. 752-768 ◽  
Author(s):  
M. José Gómez-Lechón ◽  
Laia Tolosa ◽  
M. Teresa Donato
Keyword(s):  
Risk Assessment ◽  
Metabolic Activation ◽  
New Drugs ◽  
Drug Induced ◽  
Safety Risk

scholarly journals Efficacy, metabolism and pharmacokinetics of Ro 15-5458, a forgotten schistosomicidal 9-acridanone hydrazone

2020 ◽  
Vol 75 (10) ◽  
pp. 2925-2932
Author(s):  
Alexandra Probst ◽  
Cécile Häberli ◽  
Dionicio Siegel ◽  
Jianbo Huang ◽  
Seth Vigneron ◽  
...  
Keyword(s):  
Oral Dose ◽  
High Activity ◽  
Liver Microsomes ◽  
Human Hepatocytes ◽  
Pharmacokinetic Parameters ◽  
Maximum Plasma ◽  
Drug Induced ◽  
Stage Specificity ◽  
Human And Mouse

Abstract Background Treatment of schistosomiasis, a neglected disease, relies on just one partially effective drug, praziquantel. We revisited the 9-acridanone hydrazone, Ro 15-5458, a largely forgotten antischistosomal lead compound. Methods Ro 15-5458 was evaluated in juvenile and adult Schistosoma mansoni-infected mice. We studied dose–response, hepatic shift and stage specificity. The metabolic stability of Ro 15-5458 was measured in the presence of human and mouse liver microsomes, and human hepatocytes; the latter also served to identify metabolites. Pharmacokinetic parameters were measured in naive mice. The efficacy of Ro 15-5458 was also assessed in S. haematobium-infected hamsters and S. japonicum-infected mice. Results Ro 15-5458 had single-dose ED50 values of 15 and 5.3 mg/kg in mice harbouring juvenile and adult S. mansoni infections, respectively. An ED50 value of 17 mg/kg was measured in S. haematobium-infected hamsters; however, the compound was inactive at up to 100 mg/kg in S. japonicum-infected mice. The drug-induced hepatic shift occurred between 48 and 66 h post treatment. A single oral dose of 50 mg/kg of Ro 15-5458 had high activity against all tested S. mansoni stages (1-, 7-, 14-, 21- and 49-day-old). In vitro, human hepatocytes produced N-desethyl and glucuronide metabolites; otherwise Ro 15-5458 was metabolically stable in the presence of microsomes or whole hepatocytes. The maximum plasma concentration was approximately 8.13 μg/mL 3 h after a 50 mg/kg oral dose and the half-life was approximately 4.9 h. Conclusions Ro 15-5458 has high activity against S. mansoni and S. haematobium, yet lacks activity against S. japonicum, which is striking. This will require further investigation, as a broad-spectrum antischistosomal drug is desirable.

Sign in / Sign up

Export Citation Format

Share Document