Validation of a conscious rat model for the discovery of novel agents that inhibit gastric acid secretion.
Identification of novel drug molecules requires the extensive evaluation in vitro and in vivo. Following in vitro evaluation it is necessary to efficiently screen numerous novel molecules in vivo using relatively simple methodology that requires small numbers of animals, is rapid to perform, and provides results that can definitely discriminate potential candidates for further investigation. Herein, we describe the results of three standard compounds (omeprazole, a proton pump inhibitor; cimetidine, an histamine H(2) receptor antagonist; and AR-H047108, a potassium competitive acid blocker) in the rat aspiration model (under both basal and stimulated conditions), and compared the effects with those in the pyloric ligation model with a view to comparing the results in terms of sensitivity, robustness and simplicity of the methodology. In the aspiration model, drug or vehicle was administered orally 1 h prior to administration of pentagastrin or dimaprit. Ten minutes later 0.9% NaCl was administered orally and immediately recovered by aspiration. In the pyloric ligation model, drugs or vehicle were administered orally 2 h before ligation in a volume of 10 ml/kg. For each model, the volume of each sample was measured and the acidity was determined. In the aspiration model under basal acid secretion or following stimulation with pentagastrin omeprazole, cimetidine and AR-H047108 produced dose related inhibition of acidity. Omeprazole and cimetidine inhibited acid secretion following stimulation with dimaprit. In the pyloric ligation model omeprazole, cimetidine and AR-H047108 inhibited acid secretion. The profile of each of 3 inhibitors of acid secretion exhibited similar effects irrespective of the degree of stimulation (dimaprit, pentagastrin or pyloric ligation). Thus, based on these robust effects and ease of methodology we would recommend the use of the rat aspiration model with pentagastrin stimulation of gastric acid secretion as the primary in vivo methodology to screen novel inhibitors of acid secretion.
Campbell
Colin A
CA
GI Research, Neurology & GI Centre of Excellence of Drug Discovery, GlaxoSmithKline, Harlow, Essex, UK. Colin.A.Campbell@gsk.com <Colin.A.Campbell@gsk.com>
Gaskin
Pamela J
PJ
Darton
Jill
J
Chiu
Peter
P
Lee
Kevin
K
McLean
Peter G
PG
D000284:Administration, Oral; D000818:Animals; D002927:Cimetidine / Q000494:pharmacology; D003243:Consciousness; D017259:Dimaprit / Q000008:administration & dosage; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005744:Gastric Acid / Q000378:metabolism*; D005745:Gastric Acidity Determination; D005753:Gastric Mucosa / Q000378:metabolism; D005765:Gastrointestinal Agents / Q000008:administration & dosage / Q000494:pharmacology*; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008026:Ligation; D008297:Male; D023421:Models, Animal; D009853:Omeprazole / Q000494:pharmacology; D010418:Pentagastrin / Q000008:administration & dosage; D054328:Proton Pump Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015203:Reproducibility of Results; D013270:Stomach / Q000187:drug effects* / Q000601:surgery; D013396:Suction
C514934:2,3-dimethyl-8-(2-ethyl-6-methylbenzylamino)imidazo(1,2-a)pyridine-6-carboxamide; D005765:Gastrointestinal Agents; D006635:Histamine H2 Antagonists; D007093:Imidazoles; D054328:Proton Pump Inhibitors; D011725:Pyridines; D002927:Cimetidine; D010418:Pentagastrin; D009853:Omeprazole; D017259:Dimaprit