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 resulting in enhanced absorption of a drug due to increased solubilisation. This possible influence of bile salts following stimulation of gallbladder emptying via the release of cholecystokinin on the pharmacokinetics of a sustained-release theophylline (CAS 58-55-9) preparation (Bronchoretard) was evaluated in this study. An open, randomised 3-way cross-over study in 12 healthy, non-smoking volunteers was selected to prove or reject this hypothesis. All subjects received 500 mg of the sustained-release theophylline formulation under two different cholagogia stimulating test conditions and under a fasting reference condition. A standard breakfast and i.m. application of cholecystokinin enabled modulation of bile flow; a moderate and extreme contraction of the gallbladder could be induced after a standard breakfast and after i.m. application of cholecystokinin, respectively. Following a standard breakfast, gallbladder volumes were approximately halved (50.6%) compared to the baseline volume after 79 min. Injection of 0.3 micrograms/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 constant under fasting conditions. This manipulation of bile flow did not influence concentration/time profiles of the sustained-release theophylline preparation compared to the fasting condition. Even almost complete evacuation of the gallbladder after application of cholecystokinin did not modify concentration/time profiles of theophylline in a relevant way. An unintentional rapid release of theophylline could be excluded for this sustained-release formulation for all three treatments, as not 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 the sustained-release formulation tested.
Fuchs
W S
WS
Klinge Pharma GmbH, Munich, Germany.
von Nieciecki
A
A
Molz
K H
KH
Popescu
G
G
Weil
A
A
Barkworth
M F
MF
Gay
S
S
Laicher
A
A
Stanislaus
F
F
D000328:Adult; D019540:Area Under Curve; D001646:Bile / Q000378:metabolism; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002766:Cholecystokinin / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D005215:Fasting / Q000378:metabolism; D005704:Gallbladder / Q000000981:diagnostic imaging / Q000502:physiology; D016473:Gallbladder Emptying / Q000187:drug effects / Q000502:physiology*; D006207:Half-Life; D006801:Humans; D008297:Male; D013806:Theophylline / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013810:Therapeutic Equivalency; D014463:Ultrasonography
D001993:Bronchodilator Agents; D003692:Delayed-Action Preparations; D002766:Cholecystokinin; D013806:Theophylline