title: Gastrointestinal Safety Pharmacology in Drug Discovery and Development.
abstract: Although the basic structure of the gastrointestinal tract (GIT) is similar across species, there are significant differences in the anatomy, physiology, and biochemistry between humans and laboratory animals, which should be taken into account when conducting a gastrointestinal (GI) assessment. Historically, the percentage of cases of drug attrition associated with GI-related adverse effects is small; however, this incidence has increased over the last few years. Drug-related GI effects are very diverse, usually functional in nature, and not limited to a single pharmacological class. The most common GI signs are nausea and vomiting, diarrhea, constipation, and gastric ulceration. Despite being generally not life-threatening, they can greatly affect patient compliance and quality of life. There is therefore a real need for improved and/or more extensive GI screening of candidate drugs in preclinical development, which may help to better predict clinical effects. Models to identify drug effects on GI function cover GI motility, nausea and emesis liability, secretory function (mainly gastric secretion), and absorption aspects. Both in vitro and in vivo assessments are described in this chapter. Drug-induced effects on GI function can be assessed in stand-alone safety pharmacology studies or as endpoints integrated into toxicology studies. In silico approaches are also being developed, such as the gut-on-a-chip model, but await further optimization and validation before routine use in drug development. GI injuries are still in their infancy with regard to biomarkers, probably due to their greater diversity. Nevertheless, several potential blood, stool, and breath biomarkers have been investigated. However, additional validation studies are necessary to assess the relevance of these biomarkers and their predictive value for GI injuries.
authors.affiliation: Faculty of Medicine, Department of Medical Sciences, Uppsala University, 751 85, Uppsala, Sweden.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Al-Saffar
authors.forename: André
authors.initials: A
authors.lastname: Nogueira da Costa
authors.forename: Annie
authors.initials: A
authors.lastname: Delaunois
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Leishman
authors.forename: Louise
authors.initials: L
authors.lastname: Marks
authors.forename: Marie-Luce
authors.initials: ML
authors.lastname: Rosseels
authors.forename: J-P
authors.initials: JP
authors.lastname: Valentin
mesh_terms: D000818:Animals; D015415:Biomarkers; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004335:Drug and Narcotic Control; D005746:Gastric Emptying / Q000187:drug effects; D005769:Gastrointestinal Motility / Q000187:drug effects; D041981:Gastrointestinal Tract / Q000033:anatomy & histology / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects
chemical_list: D015415:Biomarkers