EFFECT OF GALLBLADDER CONTRACTION INDUCED CHOLAGOGIA ON THE PHARMACOKINETIC PROFILE OF A SUSTAINED-RELEASE THEOPHYLLINE FORMULATION

Bile excretion might change the physiological milieu of the duodenum r esulting in enhanced absorption of a drug due to increased solubilisat ion, This possible influence of bile salts following stimulation of ga llbladder emptying via the release of cholecystokinin on the pharmacok inetics of a sustained-release theophylline (GAS 58-55-9) preparation (Bronchoretard(R)) was evaluated in this study. An open, randomised, 3 -way cross-over study in 12 healthy non-smoking volunteers was selecte d to prove or reject this hypothesis. All subjects received 500 mg of the sustained-release theophylline formulation under two different cho lagogia stimulating test conditions and under a fasting reference cond ition. A standard breakfast and i.m, application of cholecystokinin en abled a reproducible modulation of bile now: a moderate ana extreme co ntraction of the gallbladder could be induced after a standard breakfa st and after i.m. application of cholecystokinin, respectively. Follow ing a standard breakfast, gallbladder volumes were approximately halve d (50.6 %) compared to the baseline volume after 79 min. Injection of 0.3 mu g/kg body weight cholecystokinin resulted in quick and complete gallbladder evacuation (94.6 %) 36 min after the application of this cholagogue stimulus. Gallbladder volumes remained approximately consta nt under fasting conditions. This manipulation of bile flow did not in fluence concentration/time profiles of the sustained-release theophyll ine preparation compared to the fasting condition, Even almost complet e evacuation of tile gallbladder after application of cholecystokinin did not modify concentration/time profiles of theophylline in a releva nt way. An unintentional rapid release of theophylline could be exclud ed for this sustained release formulation for all three treatments, as nut a single case of dose-dumping was observed. Furthermore in vitro dissolution investigations using surfactants are neither predictive of food effects nor bile influence on in vivo absorption at least for th e sustained-release formulation rested.