Fuchs W S, von Nieciecki A, Molz K H, Popescu G, Weil A, Barkworth M F, Gay S, Laicher A, Stanislaus F
Klinge Pharma GmbH, München.
Arzneimittelforschung. 1998 May;48(5A):597-604.
Bile excretion changes the physiological milieu of the duodenum, possibly resulting in enhanced absorption of a drug due to increased solubilisation. This possible influence of bile salts following stimulation of gallbladder emptying by 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 crossover 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 compared with a fasting reference condition. A standard breakfast and i.m. administration of cholecystokinin enabled a reproducible modulation of bile flow: a moderate and extreme contraction of the gallbladder could be induced after a standard breakfast and after i.m. administration 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 microgram/kg body weight cholecystokinin resulted in fast and complete gallbladder evacuation (94.6%) 36 min after the application of this cholagogue stimulus. Gallbladder volumes remained more or less 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 administration of cholecystokinin did not modify the concentration/time profile 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 synthetic surfactants can predict neither food effects nor bile influence on the in vivo absorption at least for the sustained release formulation tested.
胆汁排泄会改变十二指肠的生理环境，可能因增溶作用增强而导致药物吸收增加。本研究评估了胆囊收缩素释放刺激胆囊排空后，胆盐对缓释茶碱（CAS 58 - 55 - 9）制剂（Bronchoretard）药代动力学的这种可能影响。选取12名健康、不吸烟的志愿者进行一项开放、随机、三交叉研究，以验证或否定这一假设。与空腹参考条件相比，所有受试者在两种不同的利胆刺激试验条件下接受500 mg缓释茶碱制剂。标准早餐和肌内注射胆囊收缩素能够实现胆汁流量的可重复调节：标准早餐后和肌内注射胆囊收缩素后，分别可诱导胆囊适度和剧烈收缩。标准早餐后，79分钟时胆囊体积与基线体积相比约减半（50.6%）。注射0.3微克/千克体重的胆囊收缩素后，在施加该利胆刺激36分钟后胆囊快速且完全排空（94.6%）。空腹条件下胆囊体积基本保持不变。与空腹条件相比，这种胆汁流量的调节并未影响缓释茶碱制剂的浓度/时间曲线。即使注射胆囊收缩素后胆囊几乎完全排空，也未对茶碱的浓度/时间曲线产生显著影响。对于所有三种治疗，该缓释制剂均可排除茶碱的意外快速释放，因为未观察到一例剂量倾泻情况。此外，至少对于所测试的缓释制剂，使用合成表面活性剂的体外溶出研究既无法预测食物影响，也无法预测胆汁对体内吸收的影响。
