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Reactive Metabolites Cause Idiosyncratic Drug-Induced Liver Injury via Inflammasome Activation in Antigen-Presenting Cells.
J Appl Toxicol
January 2025
Department of Pharmacotherapeutics and Toxicology, Faculty of Pharmacy, Osaka Medical and Pharmaceutical University, Osaka, Japan.
Although the pathophysiology of idiosyncratic drug-induced liver injury (IDILI) is unclear, it is presumed to be immune-mediated, involving complex interactions between drug metabolism and activation of the immune system. The following four reactive metabolite production patterns are considered: (1) parent compounds into reactive metabolites within neutrophils or antigen-presenting cells (APCs), (2) reactive metabolites produced by cytochrome P450 (CYP), (3) nonreactive metabolites produced by CYP into reactive metabolites within APCs, and (4) reactive metabolites produced by non-CYPs. Reactive metabolites indirectly activate inflammasomes in APCs, leading to IDILIs.
View Article and Find Full Text PDFDevelopment and Validation of a Novel Model to Discriminate Idiosyncratic Drug-Induced Liver Injury and Autoimmune Hepatitis.
Liver Int
February 2025
Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
Background And Aim: Discriminating between idiosyncratic drug-induced liver injury (DILI) and autoimmune hepatitis (AIH) is critical yet challenging. We aim to develop and validate a machine learning (ML)-based model to aid in this differentiation.
Methods: This multicenter cohort study utilised a development set from Beijing Friendship Hospital, with retrospective and prospective validation sets from 10 tertiary hospitals across various regions of China spanning January 2009 to May 2023.
Molecular docking to investigate HLA-associated idiosyncratic drug reactions.
Drug Metab Rev
January 2025
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Idiosyncratic drug reactions (IDRs) pose severe threats to patient health. Unlike conventionally dose-dependent side effects, they are unpredictable and more frequently manifest as life-threatening conditions, such as severe cutaneous adverse reactions (SCARs) and drug-induced liver injury (DILI). Some HLA alleles, such as , , and , are known risk factors for adverse reactions induced by multiple drugs.
View Article and Find Full Text PDFTAK-994 Mechanistic Investigation into Drug-Induced Liver Injury.
Toxicol Sci
January 2025
Takeda Development Center Americas, Inc, Cambridge, MA, USA.
The frequency of drug-induced liver injury (DILI) in clinical trials remains a challenge for drug developers despite advances in human hepatotoxicity models and improvements in reducing liver-related attrition in preclinical species. TAK-994, an oral orexin receptor 2 agonist, was withdrawn from phase II clinical trials due to the appearance of severe DILI. Here, we investigate the likely mechanism of TAK-994 DILI in hepatic cell culture systems examined cytotoxicity, mitochondrial toxicity, impact on drug transporter proteins, and covalent binding.
View Article and Find Full Text PDFA Complex Case of Acute Liver Failure Following Idiosyncratic Drug-Induced Liver Injury, Potentiated by Herpes Simplex Virus Infection.
Cureus
December 2024
Internal Medicine, Unidade Local de Saúde de São José, Lisbon, PRT.
Acute liver failure (ALF) is a rare, life-threatening condition that may be secondary to drug-induced liver injury (DILI) and certain viral infections. We present the case of a 73-year-old male with a history of fibrotic hypersensitivity pneumonitis with a progressive phenotype, type 2 diabetes mellitus, hypertension, and hyperlipidemia, who was admitted with ALF potentially secondary to DILI. Prior to admission, he was receiving therapy that may be related to idiosyncratic DILI (I-DILI) and ALF, namely nintedanib, which appears to have a most probable relation to I-DILI in this case, considering it was the most recently started drug.
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