The gastrointestinal (GI) tract has a unique feature of the large surface area (circa 400 m2), so it plays an important role in digestion and can receive high local or direct exposure to orally administered xenobiotics, vehicle, diet contaminants as well as dietary nutrients. Adverse drug reactions (ADR) involving the GI tract are significant and frequent problems, creating a major burden to patients, healthcare providers, and the pharmaceutical industry. The GI tract is an important target organ for toxicity in pre-clinical studies. The cells lining the crypts of the small intestine are proliferating rapidly in the body and therefore are sensitive to the effects of many therapeutic agents. The damage to stem cells within the intestinal crypts leads to the loss of cell and villus, the ulceration and inflammation of the epithelium, and the impairment of the GI tract integrity. In addition, an important consideration in the development of new drugs is the potential for off-target effects on the GI tract. A range of experimental animal models has been set up to detect possible deleterious effects to the GI tract and the potential risk in humans. It is reported that pre-clinical animal models were predictive of human GI adverse events in over 80% of cases.
Figure 1. Layers of the gastrointestinal tract (Al-Saffar A., 2015)
Gastrointestinal Toxicology Services at Creative Animodel
While many assessments of the GI tract are often limited to measurements of transit time and observations of vomiting or diarrhea, Creative Animodel can develop methods and techniques which enable to assess specific changes in GI function at the membrane, cell, and whole animal levels. Our models can be used to understand the potential to cause GI toxicity and define the mechanism of action. Based on these results, it may be possible to determine a dosing regimen with an improved GI safety profile.
Testing compounds are administered, signs of intestinal toxicity are monitored, and suitable analysis can be performed to determine the target cell population, mechanism of action and PK/PD response. There are some assessing readouts:Physiological readouts: weight loss, diarrhoea, mucosal bleeding/occult blood, and bowel weight to length rationHistological readouts: length and number of the crypt and villus, muscle thickness, mucositis severity/ulcer size, as well as apoptosis, differentiation, and proliferation Others: protein expression and gene expression
With years of experience, Creative Animodel offers a wide range of toxicology and safety pharmacology assays. Our gastrointestinal toxicology services provide clients with high-quality toxicity data to support drug discovery and development in a cost-effective and time-saving manner. If you have any questions or specific needs, please feel free to contact us.
1. Al-Saffar A., et al. Gastrointestinal safety pharmacology in drug discovery and development. Principles of Safety Pharmacology. Springer Berlin Heidelberg, 2015: 291-321.
2. Betton G R. A review of the toxicology and pathology of the gastrointestinal tract. Cell biology and toxicology, 2013, 29(5): 321-338.