Screening Methods for Drugs Affecting Gut Motility

Screening Methods for Drugs Affecting Gut Motility

1. Definition, scope and rationale

• Screening for gut-motility drugs is the ordered set of in vitro, ex vivo and in vivo preclinical procedures used to detect, quantify and rank the ability of a test compound to stimulate (prokinetic/laxative/propulsive) or inhibit (spasmolytic/antipropulsive/antidiarrhoeal) motor activity of the gastrointestinal tract (SK Gupta Ch.36, pp.540–5).
• The rationale is physiological: change in the absorptive, secretory and motor functions of the gut undermines human well-being, and appropriate motility along the gut plays a significant role in absorption of nutrients and water across the gastrointestinal tract (SK Gupta Ch.36, p.540).
• Drugs can stimulate or reduce intestinal motility and thereby alter the transit time of compounds across the intestine, hindering or stimulating their absorption — so a motility screen doubles as a pharmacokinetic-liability screen for co-administered drugs (SK Gupta Ch.36, p.540).
• Two conceptually different therapeutic goals are served by the same battery of models, only the direction of the endpoint changes (SK Gupta Ch.36, pp.540–5; Vogel 4e Part XI, pp.2416–33):
  • Acceleration — prokinetics for gastroparesis, GERD, post-vagotomy stasis, functional dyspepsia; laxatives/purgatives for constipation.
  • Retardation — spasmolytics (antimuscarinic and musculotropic) for colic and irritable bowel; antipropulsive/antidiarrhoeal agents (opioid-type) for diarrhoea.
• A critical methodological point running through the whole corpus: antipropulsive activity and antidiarrhoeal activity are dissociable — a compound may normalise small-intestinal propulsion without abolishing secretory diarrhoea, and vice versa; therefore both a transit model and a diarrhoea model must be run before an agent is called "antidiarrhoeal" (Vogel 4e Part XI, pp.2419, 2431 — Megens et al. 1989, 1990; Niemegeers et al. 1984).
• Screening cascade logic (implicit in the ordering of both source texts): receptor-binding/radioligand assay → isolated-tissue (organ-bath) assay → anaesthetised in-vivo assay → conscious/chronically instrumented in-vivo assay → disease-model (diarrhoea/constipation) assay. Throughput falls and physiological validity rises down the cascade.
• Scope boundary for this topic: the models below interrogate motor and propulsive function. Adjacent GI screens that use the same animals but different endpoints — antiulcer (Shay pylorus-ligation, indomethacin, ethanol), pancreatitis, experimental colitis, and emesis models — are separate screening domains (Medhi Ch.20, pp.217–21; Vogel 4e Part XI, pp.2444–56, 2469–76).