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Mol Pharm. 2018 Dec 20. doi: 10.1021/acs.molpharmaceut.8b00865. [Epub ahead of print]

Gastric and duodenal diclofenac concentrations in healthy volunteers after intake of the FDA standard meal: in vivo observations and in vitro explorations.

Abstract

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 on the gastrointestinal behavior of diclofenac, five healthy volunteers were recruited into a clinical study. Twenty minutes prior to diclofenac ingestion (CataflamĀ®, 50 mg 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 media 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 solid foods 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.

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