Gastrointestinal Physiology-Regulated Dogs : Utilization of a Bioavailability Study of a New Thieno[3, 2-f][1, 2, 4]triazolo[4, 3-a][1, 4]-diazepine, an Antagonist of Platelet-Activating Factor, and Its Preparations

Abstract

The gastrointestinal (GI) physiology of beagle dogs was effectively regulated with a combined treatment using intramuscular pentagastrin (10 μg/kg×2) and intravenous atropine sulfate (0.02 mg/kg×1). The superiority of the GI physiology regulated-dogs over the intact dogs was confirmed by comparative bioavailability studies using two classes of preparations of poorly water-soluble 4-(2-chlorophenyl)-2-[2-(4-isobutylphenyl)ethyl]-6, 9-dimethyl-6H-thieno[3, 2-f][1, 2, 4]triazolo[4, 3-a][1, 4]diazepine (Y-24180). Both the fine granules and the tablets of Y-24180 exhibited similar absorption profiles in the intact dogs, whereas the latter preparations revealed a delayed plasma curve of the drug in the regulated-dogs. The absorption profiles of the two classes of Y-24180 preparations in the regulated-dogs simulated those in healthy volunteers. The combined-treatment of beagle dogs with pentagastrin and atropine sulfate was suggested to supply a useful animal model for predicting the absorption characteristics of poorly water-soluble drugs and their preparations in humans.