Article pubs.acs.org/molecularpharmaceutics
Intragastric Volume Changes after Intake of a High-Caloric, High-Fat Standard Breakfast in Healthy Human Subjects Investigated by MRI Mirko Koziolek,† Michael Grimm,† Grzegorz Garbacz,‡ Jens-Peter Kühn,§ and Werner Weitschies*,† †
Institute of Pharmacy, Department of Biopharmaceutics and Pharmaceutical Technology, Center of Drug Absorption and Transport (C_DAT), Ernst Moritz Arndt University of Greifswald, Felix-Hausdorff-Straße 3, D-17487 Greifswald, Germany ‡ Physiolution GmbH, Walther-Rathenau-Straße 49a, D-17489 Greifswald, Germany § University Medicine Greifswald, Department of Radiology and Neuroradiology, Ernst Moritz Arndt University of Greifswald, Ferdinand-Sauerbruch-Straße, D-17475 Greifswald, Germany ABSTRACT: The aim of this magnetic resonance imaging (MRI) study was to investigate gastric emptying after intake of a high-caloric and high-fat standard meal as recommended by FDA and EMA for food-effect bioavailability and fed bioequivalence studies. Twelve healthy human subjects (7 male, 5 female) received the standard meal after an overnight fast. MRI was performed before as well as 15, 25, 35, 45, 55, 65, 105, 195, 275, and 375 min after meal intake using strong T2-weighted sequences and chemical shift imaging. In addition, 30 min after the beginning of meal intake subjects ingested 240 mL of water representing the recommended coadministration of water during drug intake. Gastric content volume was assessed using T2-weighted images, and fat fraction was estimated using a calculation of fat fraction in chemical shift imaging. In addition, the existence of a mechanism allowing fast gastric emptying of water in the fed state was investigated. After a lag phase of 50−90 min, gastric content volume decreased constantly with a rate of 1.7 mL/min. The water ingested 30 min after the start of the meal intake directly reached the antrum and subsequently was emptied quickly from the human stomach. Complete gastric emptying within 6 h was observed in only one out of 12 subjects. The fat fraction of the intragastric chyme decreased from 9.5% directly after meal intake to 6.3% at the end of the experiments. Moreover, the fat fraction in fundus was significantly higher compared to the antrum. This study contributes fundamental data for the assessment of food effects of solid oral dosage forms. KEYWORDS: fed stomach, food effect, gastric emptying, magnetic resonance imaging, high-fat meal, intragastric drug release, stomach road, Magenstrasse
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INTRODUCTION Reasons for the occurrence of food effects on drug absorption as well as on drug release behavior are manifold.1,2 However, the comprehension of gastric food processing is a prerequisite for understanding food effects on drug release from solid oral dosage forms, because in most cases drug dissolution starts in the stomach owing to higher liquid volumes and longer transit times compared to oral cavity and esophagus. Although the stomach is not the site of drug absorption, it should be noted that intragastric release rates, gastric mixing, and gastric transit times of solid oral dosage forms are often crucial for the drug plasma profile. To enable mixing and digestion of food, numerous aspects of gastric function are altered in the fed state compared to the fasted state. Changed physicochemical (e.g., pH value, liquid volume) and mechanical (e.g., dosage form movement, pressure) conditions combined with prolonged gastric residence time caused by the delay of gastric emptying can result in different drug release profiles compared to the fasted state.3 Thus, the understanding of gastric food digestion can support the rational development of new oral dosage forms as well as the design and assessment of clinical trials. Several © 2014 American Chemical Society
imaging techniques such as scintigraphy, ultrasound, magnetic marker monitoring, capsule endoscopy, and magnetic resonance imaging (MRI) are valuable for the assessment of gastric function. Especially MRI offers a broad field of application including accurate quantification of gastric volumes, evaluation of gastric motility, and assessment of intragastric drug distribution and gastric emptying.4,5 The rate of gastric emptying is a key factor for oral drug delivery since it controls the amount of drug that is delivered to the duodenum as the site of absorption for many pharmaceutical compounds. In the fed state, only liquids and small particles (
