Drug transport and transport-metabolism interplay in the human and rat intestine: ex vivo studies with precision-cut intestinal slices

The intestine plays an important role in uptake and metabolism of physiological, but also xenobiotic compounds, such as medical drugs. This function is supported by specialized transporters and metabolic enzymes. Together these proteins determine the concentration of compounds in intestinal cells and, as such, of the availability for uptake in the body. On the other hand there exist compounds that are able to disturb the function of these proteins or the interplay between them. This can lead to drug toxicity on the one hand, or decreased efficacy on the other hand, because blood plasma levels of substrates of transporters or metabolic enzymes can change markedly. Therefore, it is important to predict whether newly developed drugs could be inhibitors or substrates of these proteins.
In this thesis it is shown that thin slices (precision-cut intestinal slices, PCIS) prepared from intestinal tissue of rats and humans could function as a model to test drugs on their potency to interact with transport proteins and metabolizing enzymes. Also, PCIS showed the effect of inhibition of P-glycoprotein, a transporter that removes compounds from intestinal cells and transports them back into the intestinal lumen, in various segments of the human intestine. PCIS were also used to study the bile acid transporter ASBT, which is a potential new target in the treatment of diabetes. Because ASBT appeared to be functional in PCIS, this model can be used to study inhibitors and substrates of this protein. PCIS can thus be used to develop safer drugs, better predict the situation in humans and limit laboratory animal use in drug research and development.