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Gastric and Duodenal Diclofenac Concentrations in Healthy Volunteers after Intake of the FDA Standard Meal: In Vivo Observations and in Vitro Explorations
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2018-12-20 00:00:00 , DOI: 10.1021/acs.molpharmaceut.8b00865
Jari Rubbens 1 , Joachim Brouwers 1 , Jan Tack 2 , Patrick Augustijns 1
Affiliation  

This study investigated gastrointestinal drug concentrations of the weakly acidic drug diclofenac when dosed to healthy volunteers after intake of the FDA standard meal. In gastrointestinal aspiration studies, postprandial conditions are usually achieved using liquid or homogenized meals. However, these liquid meals may have a substantially different impact on the gastrointestinal physiology compared to a solid meal. To evaluate the effect of a solid meal on the gastrointestinal behavior of diclofenac, five healthy volunteers were recruited into a clinical study. Twenty minutes prior to diclofenac ingestion (Cataflam, 50 mg of potassium diclofenac), the volunteers were asked to eat a solid meal with the following composition corresponding to the FDA standard meal: 2 eggs, 2 bacon strips, 2 toasts, 4 ounces of hash brown potatoes, and 8 ounces of milk. Gastric and duodenal fluids were collected as a function of time, and blood samples were collected to link the gastrointestinal behavior to systemic exposure. In vivo observations were complemented with in vitro research to obtain a mechanistic understanding of diclofenac’s intraluminal behavior. Ingestion of the solid meal resulted in intraluminal pH-profiles similar to earlier studies with a liquid meal. However, intraluminal drug disposition differed. In the stomach, a substantial fraction of diclofenac appeared dissolved, despite an unfavorable acidic pH. Successive in vitro tests suggested that the dissolution of diclofenac is higher in the complex gastric medium resulting from FDA standard meal ingestion compared to liquid meal ingestion. Despite the favorable pH and in contrast to a previous study with a liquid meal, significant amounts of non-dissolved diclofenac were observed in the intestine. Further in vitro tests revealed adsorption of dissolved diclofenac molecules to bacon fragments present in the FDA standard meal. This adsorption negatively affected the permeation of diclofenac across a physical barrier, suggesting that in vivo absorption is affected as well. Being the first time a gastrointestinal aspiration study is combined with the administration of a solid meal, the present study demonstrates that the intraluminal behavior of diclofenac (and possibly other drugs) heavily depends on the consistency and composition of the accompanied meal.

中文翻译:

摄入FDA标准餐后健康志愿者的胃和十二指肠双氯芬酸浓度:体内观察和体外探索

这项研究调查了在摄入FDA标准餐后向健康志愿者服用的弱酸性药物双氯芬酸的胃肠道药物浓度。在胃肠道抽吸研究中,通常使用流食或均餐来达到餐后状况。然而,与固体餐相比,这些液体餐可能对胃肠道生理有显着不同的影响。为了评估固体餐对双氯芬酸胃肠道行为的影响,招募了五名健康志愿者进行临床研究。摄入双氯芬酸(Cataflam,50 mg双氯芬酸钾)前二十分钟,要求志愿者吃固体食物,其成分与FDA标准食物相对应:2个鸡蛋,2个培根条,2个吐司,4盎司哈希棕色土豆,和8盎司的牛奶 收集胃和十二指肠液随时间的变化,并收集血液样本以将胃肠道行为与全身性暴露联系起来。体内观察与体外研究相辅相成,获得了对双氯芬酸腔内行为的机械理解。摄入固体粗粉会导致管腔内pH曲线,类似于早期对液体粗粉的研究。但是,管腔内药物的处置有所不同。尽管不利的酸性pH值,在胃中仍有很大一部分双氯芬酸溶解。连续的体外测试表明,相比于流食餐,双氯芬酸在FDA标准餐食摄入的复杂胃液中的溶解度更高。尽管pH值有利,并且与之前关于流食的研究相反,在肠道中观察到大量的非溶解性双氯芬酸。进一步的体外测试表明,溶解的双氯芬酸分子被FDA标准食品中存在的培根碎片吸收。这种吸附不利地影响了双氯芬酸穿过物理屏障的渗透,表明体内吸收也受到影响。作为第一次胃肠道抽吸研究与固体食物的管理相结合,本研究表明双氯芬酸(及其他药物)的腔内行为在很大程度上取决于伴随食物的稠度和成分。这种吸附不利地影响了双氯芬酸穿过物理屏障的渗透,表明体内吸收也受到影响。作为第一次胃肠道抽吸研究与固体食物的管理相结合,本研究表明双氯芬酸(及其他药物)的腔内行为在很大程度上取决于伴随食物的稠度和成分。这种吸附不利地影响了双氯芬酸穿过物理屏障的渗透,表明体内吸收也受到影响。作为第一次胃肠道抽吸研究与固体食物的管理相结合,本研究表明双氯芬酸(及其他药物)的腔内行为在很大程度上取决于伴随食物的稠度和成分。
更新日期:2018-12-20
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