Drug-induced liver injury: Interactions between drug properties and host factors

Abstract

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.

Adverse events associated with the use of direct-acting oral anticoagulants in clinical practice: beyond bleeding complications

“…In fact, although hepatotoxicity (associated with DOACs) is deemed to be idiosyncratic (ie, it may occur at therapeutic doses and cannot be explained by the pharmacological action of these drugs), the latest evidence has suggested that both host-and drug-related risk factors are likely to interact in the occurrence of DILI. 54 Among the latter, daily dose, lipophilicity, metabolic pathway mediated by cytochromes, and structural moieties with the formation of reactive metabolism have been proposed to be strong predictors of the risk in humans. 55 Notably, apixaban, rivaroxaban, and dabigatran contain structural moieties, although they are not clearly involved in the formation of known hepatotoxic reactive metabolites.…”

Unraveling cellular pathways contributing to drug-induced liver injury by dynamical modeling

“…When a cell dies, especially if this is not through apoptosis, it triggers the adaptive immune response, a process called 'sterile inflammation.' The inflammatory stress response has been suggested to play a role in the unpredictability of DILI, and the nonlinearity of drug response curves [1,32,33].…”

“…Drugs can cause DNA damage either directly or indirectly: Some drugs (mostly chemotherapeutics) directly intercalate between or covalently bind to DNA [78]. Other drugs lead to ROS that can bind to DNA and cause DNA damage, thereby indirectly activating the DNA damage response pathway [33,[79][80][81][82]. When the DNA damage is not properly repaired, it can ultimately lead to cancer.…”

“Drug-Induced Liver Injury Clinical Consortia: a global research response for a worldwide health challenge”

“…[1] The multifactorial nature of the idiosyncratic chemical damage targeting the liver depends on the interaction of the drug physicochemical properties with the host factors that make the subjects susceptible on rare instances. [2] No reliable methods for accurately predicting the occurrence of toxic liver damage on a given individual are still available. Hence, information on the true hepatic safety profile for the bulk of drugs relies on observational studies and requires the exposure of hundreds of thousands of subjects once the medication reaches the market.…”