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Abstract
Currently risk assessment is based on animal experiments with limited success.
The aim of this study was to explore the feasibility to replace the use of animals in
risk assessment for drug-induced liver injury, by hazard identification and kinetic
modeling based on human in vitro data for metabolism and toxicity. Paracetamol
was used as model compound. Human hepatocytes were used to elucidate the toxic
mechanisms by transcriptomics and metabolite formation. Time- and dose-dependent
toxicant exposure of the human liver was modeled with a mechanism-based
physiology-based toxicokinetic (PBTK) model (Simcyp®) and time and concentration-
dependent metabolite production and exposure of the hepatocytes to the toxic
reactive metabolite was modeled with an in vitro biokinetic model using experimentally
derived and literature data on metabolism. Plasma concentration profiles
were adequately modeled and the effect of individual variability in metabolism was
assessed. Phase 2 metabolism as observed in human hepatocytes was well predicted
by the biokinetic model. However the rate of phase 1 metabolism was over predicted
in both models. Pathway analysis learned that oxidative phosphorylation,
drug metabolism and immune response were consistently regulated, suggesting that
adverse effects of paracetamol are related to oxidative stress and immune dysfunction.
The results indicate the feasibility of in vitro-based risk assessment of xenobiotics
for the human population without the use of animals taking into account
the individual variation in drug metabolism. For future refinement more data on
metabolizing enzyme and transporter protein abundance is requ
Original language | English |
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Title of host publication | Proceedings of the 53rd Annual meeting and ToxExpo |
Pages | 281-281 |
Volume | SOT |
Publication status | Published - 2014 |
Event | ToxExpo, Phoenix, Arizona - Duration: 24 Mar 2014 → 27 Mar 2014 |
Conference
Conference | ToxExpo, Phoenix, Arizona |
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Period | 24/03/14 → 27/03/14 |
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Projects
- 1 Finished