title: An evaluation of the non-invasive faecal pellet assessment method as an early drug discovery screen for gastrointestinal liability.
abstract: BACKGROUND
  Gastrointestinal adverse effects contribute significantly to drug attrition as well as reduced patient compliance. Determination of gastrointestinal liability early in a compound's preclinical development would be a valuable tool. We evaluated the non-invasive faecal pellet method in the rat, assessed the feasibility of adding the endpoint to other study types and investigated correlation with the charcoal meal method.
  
  
  METHODS
  Han Wistar rats, pair housed in metabolism cages, received a single dose of vehicle, atropine, bethanechol, loperamide or metoclopramide. The number, weight and appearance of pellets produced were assessed over 10 h and at 24 h post-dose. The endpoint was also added to a modified Irwin screen (testing atropine, theophylline, clonidine, amphetamine, baclofen or quinine) and a whole body plethysmography study (testing theophylline or bethanechol). Pellets were collected from home cages out to 4 h post-dose (Irwin) or following a 45 minutes plethysmography session. To assess correlation with stomach emptying and intestinal transit charcoal meal data was generated where published data was not available.
  
  
  RESULTS
  Atropine decreased, while bethanechol and metoclopramide increased the number and weight of faecal pellets produced. Atropine produced darker, harder pellets and bethanechol lighter, softer pellets. Loperamide reduced pellet production at later time points only. Theophylline increased (Irwin and plethysmography) and atropine (Irwin) decreased pellet number and weight. Effects were maximal at the T(max) and detected in all study environments. Primary data generation was not affected by pellet collection. Pellet findings were generally comparable to charcoal meal transit data, with compounds showing an inhibition (atropine, loperamide, amphetamine, baclofen, clonidine, quinine) or stimulation (bethanechol) in both models.
  
  
  CONCLUSIONS
  We have demonstrated that the faecal pellet method can detect expected reference compound induced changes in pellet transit. The technique is a useful non-invasive 'add-on' to other study types allowing gastrointestinal effects to be flagged earlier in preclinical development.
authors.affiliation: Global Safety Assessment, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire, England SK10 4TG, UK. louise.marks@astrazeneca.com
authors.forename: Louise
authors.initials: L
authors.lastname: Marks
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Beard
authors.forename: Des
authors.initials: D
authors.lastname: Cobey
authors.forename: Nick
authors.initials: N
authors.lastname: Moore
authors.forename: Victoria
authors.initials: V
authors.lastname: Motyer
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Valentin
authors.forename: Lorna
authors.initials: L
authors.lastname: Ewart
mesh_terms: D000818:Animals; D015195:Drug Design; D005240:Feasibility Studies; D005243:Feces / Q000737:chemistry; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects*; D041981:Gastrointestinal Tract / Q000187:drug effects; D005772:Gastrointestinal Transit / Q000187:drug effects*; D008297:Male; D010993:Plethysmography, Whole Body; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D018675:Toxicity Tests / Q000379:methods*
keywords: ADRs; AEs; BPM; Charcoal meal; DRF; Faecal pellet; GI; Gastric emptying; Gastrointestinal adverse effects; Gastrointestinal safety liability; ICH; International Conference on Harmonisation; MTD; MV; Methods; NSAID; Non-invasive screen; Pellet transit; RR; SC; Small intestinal transit; TV; WBP; adverse drug reactions; adverse effects; breaths per minute; dose range finding; gastrointestinal; maximum tolerated dose; minute volume; non-steroidal anti-inflammatory drugs; respiratory rate; subcutaneous; tidal volume; whole body plethysmography