Assessing Gastrointestinal Toxicity Using Human Fresh Tissues
The prediction of gastrointestinal safety ranges from effects that are potentially life-threatening (such as gastric bleeding with NSAIDs) to those which may appear less severe (such as changes in GI motility) but can have a high impact on patient compliance1. Over 700 drugs are known to cause adverse GI effects2, ranging from minor effects to potentially serious adverse effects including ulceration, direct cytotoxicity (such as with chemotherapy), changes in secretory mechanisms that may lead to constipation or diarrhoea, or changes in the gut microflora3.
One of the most attractive features of human ex vivo tissues is the ability to obtain almost any region of the GI tract (and its accessory organs) and to study a wide range of functional end-points4. Clearly, any in vitro or ex vivo system will not reflect all features required to study the entire gastrointestinal system; however, detailed mechanistic insights are feasible. The varied functional end-points relate closely to a number of the known causes of GI toxicity including changes in ion channels (fluid secretion), motility (GI transit time and possibly nausea) and drug-drug interactions originating in the GI tract which might lead to local or even systemic adverse effects. The accurate balance of drug transporters (e.g. Pgp) and drug-metabolising enzymes is of particular importance both in avoiding species differences and in providing advantages over cell-based models such as Caco-2. Patients with pre-existing GI disease may be at greatest risk of adverse effects. A further key advantage is therefore the ability to investigate both healthy and diseased tissues; indeed, the ICHS7A guidelines on safety pharmacology studies make specific mention of consideration being given to modelling drug effects in such patients5. When considered alongside the growing interest in precision-cut intestinal slices6,7 (which increases experimental throughput) and easier access to ethically-donated tissues, human functional tissue has the potential to make a significant contribution to improved detection of GI adverse effects.
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- ICH S7A Safety pharmacology studies for human pharmaceuticals. http://www.ich.org/products/guidelines/safety/article/safety-guidelines.html
- Niu, X. et al. Evaluation of the intestinal toxicity and transport of xenobiotics utilizing precision-cut slices. Xenobiotica (2013) 43 (1) 73-83.
- de Graaf, I.A.M. et al. Preparation and incubation of precision-cut liver and intestinal slices for application in drug metabolism and toxicity studies. Nature Protocols (2010) 5, 1540-1551.