Quantification of Gastrointestinal Liquid Volumes and Distribution Following a 240 mL Dose of Water in the Fasted State

Abstract

The rate and extent of drug dissolution and absorption from solid oral dosage forms is highly dependent upon the volumes and distribution of gastric and small intestinal water. However, little is known about the time courses and distribution of water volumes in vivo in an undisturbed gut. Previous imaging studies offered a snapshot of water distribution in fasted humans and showed that water in the small intestine is distributed in small pockets. This study aimed to quantify the volume and number of water pockets in the upper gut of fasted healthy humans following ingestion of a glass of water (240 mL, as recommended for bioavailability/bioequivalence (BA/BE) studies), using recently validated noninvasive magnetic resonance imaging (MRI) methods. Twelve healthy volunteers underwent upper and lower abdominal MRI scans before drinking 240 mL (8 fluid ounces) of water. After ingesting the water, they were scanned at intervals for 2 h. The drink volume, inclusion criteria, and fasting conditions matched the international standards for BA/BE testing in healthy volunteers. The images were processed for gastric and intestinal total water volumes and for the number and volume of separate intestinal water pockets larger than 0.5 mL. The fasted stomach contained 35 ± 7 mL (mean ± SEM) of resting water. Upon drinking, the gastric fluid rose to 242 ± 9 mL. The gastric water volume declined rapidly after that with a half emptying time (T50%) of 13 ± 1 min. The mean gastric volume returned back to baseline 45 min after the drink. The fasted small bowel contained a total volume of 43 ± 14 mL of resting water. Twelve minutes after ingestion of water, small bowel water content rose to a maximum value of 94 ± 24 mL contained within 15 ± 2 pockets of 6 ± 2 mL each. At 45 min, when the glass of water had emptied completely from the stomach, total intestinal water volume was 77 ± 15 mL distributed into 16 ± 3 pockets of 5 ± 1 mL each. MRI provided unprecedented insights into the time course, number, volume, and location of water pockets in the stomach and small intestine under conditions that represent standard BA/BE studies using validated techniques. These data add to our current understanding of gastrointestinal physiology and will help improve physiological relevance of in vitro testing methods and in silico transport analyses for prediction of bioperformance of oral solid dosage forms, particularly for low solubility Biopharmaceutics Classification System (BCS) Class 2 and Class 4 compounds.

Physical chemistry of supersaturated solutions and implications for oral absorption

“…Since the pre-requisite of absorp-105 tion is the presence of drug molecules in solution, many formulation 106 approaches pre-dissolve the drug in the formulation using cosolvents 107 or surfactant-lipid blends [3]. For most solubility enhancing approaches 108 based on solid dosage forms, the theoretical basis is the Whitney-Noyes 109 equation, coupled with the Nernst-Brunner diffusion layer model, 110 which describes the dissolution of a solid: whereby the solvent is not present in the crystalline phase and is 156 given by [19,20]: following equation [21]: liquid-liquid equilibrium (LLE) [22], which enables the amorphous sol-199 ubility to be predicted, as long as the crystalline solubility is known [23].…”

Exploring gastrointestinal variables affecting drug and formulation behavior: Methodologies, challenges and opportunities

“…More recently, the attention is shifting to monitoring the in vivo environment of standard drug testing conditions. A recent study investigated gastric fluid contents under the standard fasting and fed oral dosage form testing conditions (Mudie et al, 2014, Koziolek et al, 2014. This work has been extended to the small bowel environment.…”

Development of a Novel Simplified PBPK Absorption Model to Explain the Higher Relative Bioavailability of the OROS® Formulation of Oxybutynin

“…The model assumes that fluid movements along the GI tract are driven by gastric emptying and intestinal transit time, taking into account volume fluctuations due to fluid intake, intestinal fluid secretion and reabsorption (53). The empirical nature of the model is due to the fact that the GI fluid secretion and reabsorption parameters were obtained by fitting the model to free intestinal water data (71). This data was obtained by magnetic resonance imaging (MRI) after the intake of 240 mL of water in 12 healthy volunteers under fasting conditions (71).…”

“…The empirical nature of the model is due to the fact that the GI fluid secretion and reabsorption parameters were obtained by fitting the model to free intestinal water data (71). This data was obtained by magnetic resonance imaging (MRI) after the intake of 240 mL of water in 12 healthy volunteers under fasting conditions (71). The details of the model and the fitting can be found in Sect.…”