Development of a canine model to enable the preclinical assessment of pH-dependent absorption of test compounds.
A preclinical canine model capable of predicting a compound's potential for pH-dependent absorption in humans was developed. This involved the surgical insertion of a gastrostomy feeding tube into the stomach of a beagle dog. The tube was sutured in position to allow frequent withdrawal of gastric fluid for pH measurement. Therefore, it was possible to measure pH in the stomach and assess the effect of gastric pH-modifying agents on the absorption of various test compounds. Fasted gastric pH in the dog showed considerable inter- and intra-animal variability. Pretreatment of pentagastrin (6 µg/kg intramuscularly) 20 min prior to test compound administration was determined to be adequate for simulating fasting stomach pH in humans. Pretreatment with famotidine [40 mg orally] 1 h prior to test compound administration was determined to be adequate for simulating human gastric pH when acid-reducing agents are coadministered. Pentagastrin and famotidine pretreatments were used to test two discovery compounds and distinct differences in their potential for pH-dependent absorption were observed. The model described herein can be used preclinically to screen out compounds, differentiate compounds, and support the assessment of various formulation- and prodrug-based strategies to mitigate the pH effect.
Pharmaceutical Candidate Optimization: Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08540, USA.
R Marcus
RM
Fancher
Hongjian
H
Zhang
Bogdan
B
Sleczka
George
G
Derbin
Richard
R
Rockar
Punit
P
Marathe
D000284:Administration, Oral; D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage; D004285:Dogs; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D015738:Famotidine / Q000008:administration & dosage; D005215:Fasting / Q000378:metabolism; D005750:Gastric Juice / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism*; D005774:Gastrostomy / Q000295:instrumentation; D006863:Hydrogen-Ion Concentration; D007273:Injections, Intramuscular; D007408:Intestinal Absorption / Q000187:drug effects; D008297:Male; D023421:Models, Animal; D010418:Pentagastrin / Q000008:administration & dosage; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics; D013270:Stomach / Q000187:drug effects; D013997:Time Factors
D004041:Dietary Fats; D004364:Pharmaceutical Preparations; D015738:Famotidine; D010418:Pentagastrin