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, Munich, Germany.
Arzneimittelforschung. 1996 Dec;46(12):1120-6.
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.
胆汁排泄可能会改变十二指肠的生理环境，由于药物增溶作用增强而导致其吸收增加。本研究评估了通过释放胆囊收缩素刺激胆囊排空后，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。选择12名健康、不吸烟的志愿者进行一项开放、随机的三交叉研究，以验证或否定这一假设。所有受试者在两种不同的利胆刺激试验条件下以及空腹参考条件下接受500毫克缓释茶碱制剂。一份标准早餐和肌肉注射胆囊收缩素能够调节胆汁流量；分别在标准早餐后和肌肉注射胆囊收缩素后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大约减半（50.6%）。注射0.3微克/千克体重的胆囊收缩素导致在应用这种利胆刺激物36分钟后胆囊迅速且完全排空（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。即使在应用胆囊收缩素后胆囊几乎完全排空，也未以相关方式改变茶碱的浓度/时间曲线。对于所有三种治疗，该缓释制剂均未观察到一例剂量倾泻情况，因此可以排除茶碱的意外快速释放。此外，至少对于所测试的缓释制剂，使用表面活性剂的体外溶出研究既不能预测食物效应，也不能预测胆汁对体内吸收的影响。
