Expert opinion on drug metabolism & toxicology · 2025
DILI prediction in drug development: present and future.
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Uetrecht Jack
Аннотация
INTRODUCTION: Idiosyncratic drug-induced liver injury (iDILI) results in significant patient morbidity and significantly increases the risk of drug development. The current methods to screen for iDILI risk are inadequate.
AREAS COVERED: The general mechanism of iDILI and the current methods to screen for iDILI are reviewed. Then the potential for new biomarkers is explored.
EXPERT OPINION: Better biomarkers of iDILI risk should be based on the mechanism of iDILI. In general, it is an adaptive immune response, specifically CD8+ cytotoxic T cells, that is responsible for hepatocyte cell death, not direct toxicity of the drug. Therefore, in vitro cytotoxicity assays represent an artifact not the mechanism of iDILI. Activation of the adaptive immune response leading to iDILI requires an innate immune response, in particular activation of antigen presenting cells. The innate immune response is immediate and unlikely to be idiosyncratic. For example, studies have found that incubation of hepatocytes with drugs causes the release of molecules that activate THP-1-derived macrophages. The response of hepatocytes, the release of damage-associated molecular pattern molecules (DAMPs), especially in extracellular vesicles, and the response of antigen presenting cells (APCs) are likely to provide better biomarkers of iDILI risk.
AREAS COVERED: The general mechanism of iDILI and the current methods to screen for iDILI are reviewed. Then the potential for new biomarkers is explored.
EXPERT OPINION: Better biomarkers of iDILI risk should be based on the mechanism of iDILI. In general, it is an adaptive immune response, specifically CD8+ cytotoxic T cells, that is responsible for hepatocyte cell death, not direct toxicity of the drug. Therefore, in vitro cytotoxicity assays represent an artifact not the mechanism of iDILI. Activation of the adaptive immune response leading to iDILI requires an innate immune response, in particular activation of antigen presenting cells. The innate immune response is immediate and unlikely to be idiosyncratic. For example, studies have found that incubation of hepatocytes with drugs causes the release of molecules that activate THP-1-derived macrophages. The response of hepatocytes, the release of damage-associated molecular pattern molecules (DAMPs), especially in extracellular vesicles, and the response of antigen presenting cells (APCs) are likely to provide better biomarkers of iDILI risk.