Drug-induced liver injury: Interactions between drug properties and host factors.
Idiosyncratic drug-induced liver injury (DILI) is a common cause for drug withdrawal from the market and although infrequent, DILI can result in serious clinical outcomes including acute liver failure and the need for liver transplantation. Eliminating the iatrogenic "harm" caused by a therapeutic intent is a priority in patient care. However, identifying culprit drugs and individuals at risk for DILI remains challenging. Apart from genetic factors predisposing individuals at risk, the role of the drugs' physicochemical and toxicological properties and their interactions with host and environmental factors need to be considered. The influence of these factors on mechanisms involved in DILI is multi-layered. In this review, we summarize current knowledge on 1) drug properties associated with hepatotoxicity, 2) host factors considered to modify an individuals' risk for DILI and clinical phenotypes, and 3) drug-host interactions. We aim at clarifying knowledge gaps needed to be filled in as to improve risk stratification in patient care. We therefore broadly discuss relevant areas of future research. Emerging insight will stimulate new investigational approaches to facilitate the discovery of clinical DILI risk modifiers in the context of disease complexity and associated interactions with drug properties, and hence will be able to move towards safety personalized medicine.
Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, US Food and Drug Administration, Jefferson, AR, United States.
Minjun
M
Chen
Gastroenterology, Central Arkansas Veterans Healthcare System, Little Rock, AR, United States; Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
Ayako
A
Suzuki
Center of Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany.
Jürgen
J
Borlak
Unidad de Gestión Clínica de Enfermedades Digestivas, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain. Electronic address: andrade@uma.es.
Raúl J
RJ
Andrade
Unidad de Gestión Clínica de Enfermedades Digestivas, Servicio de Farmacología Clínica, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Málaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.
M Isabel
MI
Lucena
D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D004347:Drug Interactions; D006801:Humans; D012307:Risk Factors
Clinical toxicology; Drug clearance; Drug metabolism; Drug physicochemical properties; Drug-host Interaction; Drug-induced liver injury; Host factors; Pharmacogenetics