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.
The gastrointestinal (GI) physiology of beagle dogs was effectively regulated with a combined treatment using intramuscular pentagastrin (10 micrograms/kg x 2) and intravenous atropine sulfate (0.02 mg/kg x 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.
Sagara
K
K
Research Laboratories, Yoshitomi Pharmaceutical Industries, Ltd., Fukuoka, Japan.
Yamada
I
I
Kawazoe
Y
Y
Mizuta
H
H
Shibata
M
M
D000284:Administration, Oral; D000818:Animals; D001285:Atropine / Q000008:administration & dosage / Q000494:pharmacology; D001381:Azepines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004304:Dosage Forms; D006801:Humans; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects; D008297:Male; D010418:Pentagastrin / Q000008:administration & dosage / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D012995:Solubility; D013607:Tablets; D014230:Triazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D001381:Azepines; D004304:Dosage Forms; D010972:Platelet Activating Factor; D013607:Tablets; D014230:Triazoles; C068035:4-(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; D001285:Atropine; D010418:Pentagastrin