Screening Methods for Drugs Affecting Gut Motility

Introduction & scope

• Definition — the ordered in-vitro, ex-vivo and in-vivo procedures used to detect, quantify and rank a compound's ability to stimulate (prokinetic, laxative) or inhibit (spasmolytic, antipropulsive) gastrointestinal motor activity.
• Rationale — motility governs absorption of nutrients and water; drugs alter transit time and hence drug absorption, so a motility screen doubles as a pharmacokinetic-liability screen.
• Two directions, one battery — only the sign of the endpoint changes — acceleration (prokinetics for gastroparesis and GERD, laxatives for constipation) versus retardation (spasmolytics for colic and IBS, opioid-type antipropulsives for diarrhoea).
• The governing rule — antipropulsive and antidiarrhoeal activity are dissociable — a transit model and a diarrhoea model must both be run before an agent may be called antidiarrhoeal.
• Cascade logic — receptor binding → organ bath → anaesthetised in vivo → conscious in vivo → disease model; throughput falls and physiological validity rises down the cascade. Effects are readable at four levels — receptor occupancy, tension or pressure, myoelectric spiking, and net propulsion of a marker.