INFLUENCE OF PHYSICAL FACTORS IN GASTROINTESTINAL-TRACT ON ACETAMINOPHEN RELEASE FROM CONTROLLED-RELEASE TABLETS IN FASTED DOGS

Four types of controlled-release (CR) acetaminophen (AAP) tablets, nam ely A, B, C and D, were prepared to investigate the influence of physi cal factors in the gastrointestinal (GI) tract on AAP release in faste d dogs. CR-A was designed as a completely resistant formulation to mec hanical destructive force but to show an agitation speed-dependent dis solution rate. CR-B, CR-C and CR-D were designed to have different wet strengths but to show similar dissolution rates. The absorption profi les of the four CR forms in dogs showed biphasic patterns, with phase change about 2 h after oral dosing. The first phase of the absorption profile of CR-A and in vivo release directly observed were close to it s in vitro profiles at a speed of 25-50 revs./min, indicating that agi tation intensity in the dog GI tract may be relatively low. The first phase of the absorption profiles of the CR-B, CR-C and CR-D differed f rom each other, despite the fact that dissolution rates in vitro were similar. The tablet with low wet strength showed a faster absorption r ate, indicating that it would be destructed by GI mechanical forces. F urthermore, absorption during the second phase was extremely low for a ll CR tablets. We confirmed on necroscopy that the suppression of drug absorption in the second phase was caused by the termination of AAP r elease from the tablets in the colon. These results will be useful in evaluating the in vivo performance of CR tablets in fasted dogs.