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Precision-cut intestinal slices as an ex vivo model to study NSAID-induced intestinal toxicity

PhD ceremony:Ms X. (Xiaoyu) Niu
When:October 24, 2014
Supervisor:prof. dr. G.M.M. (Geny) Groothuis
Co-supervisor:dr. ir. I.A.M. (Inge) de Graaf
Where:Academy building RUG
Faculty:Science and Engineering
Precision-cut intestinal slices as an ex vivo model to study
NSAID-induced intestinal toxicity

Precision cut intestinal slices (PCIS) are an unique intestinal ex vivo model, which contains all the intestinal cell types in their natural matrix, and maintains high activities of metabolic enzymes and transporters. Since drug-induced toxicity is usually a result of interaction between multiple cell types, and drug metabolism and transport play a critical role in toxicity, PCIS are a promising model to study drug-induced toxicity ex vivo. Up to now, the application of PCIS for the evaluation of drug toxicity is still in its infancy. Therefore, in the thesis of Xiaoyu Niu the applicability of PCIS to study non-steroidal anti-inflammatory drugs (NSAIDs)-induced intestinal toxicity was investigated. In her thesis she showed that the cellular pathways involved in the mechanism of diclofenac (DCF) intestinal toxicity were correctly reflected in PCIS. In addition, species differences in the extent of metabolism and toxicity of DCF were evident in rat and human PCIS. Extensive metabolism of DCF occurred in the human intestine, but these metabolites were not the cause of DCF jejunum toxicity. By using PCIS of Mrp2 deficient rats Niu could determine the effects of this deficiency on DCF disposition and toxicity without the influence of the liver. Taken together Niu’s studies described in her thesis have shown that PCIS are a valuable translational model to detect drug-induced intestinal toxicity and to study the toxic mechanisms ex vivo. Using PCIS obtained from both humans and animals in preclinical research will result in a better prediction of toxicity during drug development and will help to reduce the animal use in research.