Gastrointestinal-tract models and techniques for use in safety pharmacology

Abstract

The gastrointestinal tract (GI tract), which extracts nutrients, electrolytes, minerals, and water, is prone to injury as a result of oral drug administration. Clinical assessment of the GI tract is often limited to measurements of transit time and observations of vomiting or diarrhoea, despite the existence of methods and techniques capable of assessing specific changes in GI function at the membrane, cell, and whole animal levels. Membrane studies, record the uptake of solutes, and electrolyte transport, assessing the affects of compounds on transepithelial GI transport and flux. Such methods lend themselves to permeability, immunohistochemistry, morphology, and molecular biology techniques. Isolated cells from the GI tract or cultured cell lines provide knowledge of regulation and function at a cellular level, whilst motility patterns, taken in vivo or from biopsies, provide information at a more integrated level. In anesthetised animals, ligated segments of the intestine can be infused with test compounds, providing information about absorptive and secretory processes important for the treatment of diarrhoea. Computer simulations and modelling are used to predict the disposition of a chemical and its metabolite and can, to some extent, replace animal testing, thereby reducing development costs. Indeed, software programs can be used to simulate the dissolution, absorption, distribution, metabolism, and excretion (ADME) properties of potential drugs in the human GI tract. Finally, advances in the field of imaging, combined with endoscopy, have resulted in a wireless capsule, allowing the inspection of the GI tract anatomy and pathology without surgical intervention. It is concluded that the field of safety pharmacology could rapidly, cheaply, and routinely incorporate membrane, isolated tissue, and endoscopy techniques for GI tract testing of drugs.