Mechanistic Fluid Transport Model to Estimate Gastrointestinal Fluid Volume and Its Dynamic Change Over Time
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Research Article Theme: Advances and Applications of In Vivo Medical Imaging in Drug Development and Regulation Guest Editors: Peng Zou, Doanh Tran, and Edward Bashaw
Mechanistic Fluid Transport Model to Estimate Gastrointestinal Fluid Volume and Its Dynamic Change Over Time Alex Yu,1 Trachette Jackson,2 Yasuhiro Tsume,1 Mark Koenigsknecht,1 Jeffrey Wysocki,3 Luca Marciani,4 Gordon L. Amidon,1 Ann Frances,1 Jason R. Baker,3 William Hasler,3 Bo Wen,1 Amit Pai,5 and Duxin Sun1,6,7,8
Received 2 May 2017; accepted 1 September 2017
Gastrointestinal (GI) fluid volume and its dynamic change are integral to study drug disintegration, dissolution, transit, and absorption. However, key questions regarding the local volume and its absorption, secretion, and transit remain unanswered. The dynamic fluid compartment absorption and transit (DFCAT) model is proposed to estimate in vivo GI volume and GI fluid transport based on magnetic resonance imaging (MRI) quantified fluid volume. The model was validated using GI local concentration of phenol red in human GI tract, which was directly measured by human GI intubation study after oral dosing of nonabsorbable phenol red. The measured local GI concentration of phenol red ranged from 0.05 to 168 μg/mL (stomach), to 563 μg/mL (duodenum), to 202 μg/mL (proximal jejunum), and to 478 μg/mL (distal jejunum). The DFCAT model characterized observed MRI fluid volume and its dynamic changes from 275 to 46.5 mL in stomach (from 0 to 30 min) with mucus layer volume of 40 mL. The volumes of the 30 small intestine compartments were characterized by a max of 14.98 mL to a min of 0.26 mL (0–120 min) and a mucus layer volume of 5 mL per compartment. Regional fluid volumes over 0 to 120 min ranged from 5.6 to 20.38 mL in the proximal small intestine, 36.4 to 44.08 mL in distal small intestine, and from 42 to 64.46 mL in total small intestine. The DFCAT model can be applied to predict drug dissolution and absorption in the human GI tract with future improvements. Abstract.
KEY WORDS: compartmental absorption and transit; dynamic; gastrointestinal tract; mechanistic model; oral absorption.
INTRODUCTION Electronic supplementary material The online version of this article (https://doi.org/10.1208/s12248-017-0145-x) contains supplementary material, which is available to authorized users. 1
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, USA. 2 Department of Mathematics, College of Literature, Science, and the Arts, University of Michigan, Ann Arbor, Michigan 48109, USA. 3 Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan 48109, USA. 4 Nottingham Digestive Diseases Centre and NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals and the University of Nottingham, Nottingham, NG7 2UH, UK. 5 Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109, USA. 6 College of Pharmacy, Tianjin Medical University, Tianjin, People’s Rep
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