胃内pHコントロールしたビーグル犬のBenzimidazole Sulfoxide誘導体のToxicokineticsへの応用

抄録

The bioavailability (BA) of E3810, an unstable compound in acid, was studeid by controlling gastric pH in beagle dogs. The BAs, after the administration of E3810 solution orally to dogs with a low or a high gastric pH, were 3.16 ± 1.28% and 76.4 ± 13.8%, respectively. These results suggested that E3810 decomposes rapidly in the presence of gastric acid, but its BA is high if the decomposition of E3810 is avoided in the gastrointestinal tract. To establish a dosage form of E3810 for toxicity testing in the dog, E3810 enteric-coated tablets (ϕ=6.5 mm) and E3810 solution were administered. The t_max after the administration of E3810 enteric-coated tablets was prolonged (t_max=5.42 hr), suggesting a slow gastric emptying, or a delay in the release of E3810. In contrast, when the tablets were asministered orally to fasted beagle dogs, t_max was obtained within 1 hr, suggesting rapid release once the tablet left the stomach. After administration of E3810 solution to beagle dogs with a high gastric pH, the BA was high, with the lowest variability. In the preliminary toxicity test, E3810 solution was administered to dogs with a high gastric pH once a day for seven days. The plasma concentrations of E3810 on day 1 and day 7 increased dose-dependently, and there is no difference in pharmacokinetics between day 1 and day 7. These results indicate that the method to control gastric pH in dogs is useful for the dosing of a compound that is unstable in gastric acid.