Tuesday, 02 July 2019 14:42

New in-vitro/in-silico method predicts drug-induced liver injury Featured

An international team with participation of the Leibniz Research Centre for Working Environment and Human Factors at the Technical University of Dortmund (IfADo) has established an in vitro/in silico method to predict drug-induced liver injury with regard to oral doses and blood concentrations.  


There are lots of animal data, but there are currently no reliable thresholds concentration values for humans, at which toxicity begins (LOAELs, lowest observed adverse effect level) as well as none data about of non-toxicity, (NOAELs, non observed adversed effect level). Therefore, the scientists have optimized an in-vitro system by integrating novel test metrics. A so-called toxicity separation index indicates how well a test ca differentiate between liver-toxic effects and non liver-toxic effects; a toxicity estimation index characterizes how well liver-toxic effects in in vivo-blood concentrations can be estimated.

The scientists worked with primary human liver cells from three different donors. The cells were exposed to the test substances in five different concentrations. Then, the cells were examined for cytotoxicity and oxidative stress; relevant genes were selected from a gene expression profile and integrated in the model. For each of the test substances, a physiology-based pharmacokinetic (PBPK) model was developed. In doing so, the computer program takes into account how the human organism is metabolizing a substance. This can be used, for example, to calculate the maximum blood concentration of a test compound. A risk of drug-induced liver damage can be estimated if the maximum blood concentration (Cmax) of the test compound is known. The acceptable daily dosage (ADI) can be estimated even if information on the blood concentration are not present.

After optimization and testing of the new model, the effects of 28 substances of already known liver toxicity could all be accurately predicted with the exception of two non-toxic substances. The system also provided valuable information on which genes are relevant in the in vivo-toxicity of human primary liver cells and which the optimal incubation time is.

Now the scientists want to test further substances.

The system is to be used to sort out unsuitable substances in advance that then won't be used in animal experiments.

The researchers have published their development in the Journal Archives of Toxicology: Albrecht, W., Kappenberg, F., Brecklinghaus, T. et al.: Prediction of human drug-induced liver injury (DILI) in relation to oral doses and blood concentration. Arch Toxicol (2019). doi: 10.1007/s00204-019-02492-9 (Open Access)

Further information:
https://www.ifado.de/blog/2019/07/01/tierversuche-alternative-aus-kulturschale/
http://av-media.vu.nl/mediasite/Play/edd072bf01c94fe6adc7279ed0604ea61d Video of a talk at "10th Symposium of the Section of Pharmaceutical Toxicology of the Dutch Society of
Toxicology (NVT)" (11th April 2019, Amsterdam)