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.

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Key Messages• Previous measurements of regional colonic volume have used invasive methods that could disturb natural morphology.• Using MRI, volume measurement of the undisturbed colon was achieved in 75 healthy volunteers and 25 IBS-D patients. Normal volume ranges were defined.• IBS-D patients showed less ability to accommodate post-prandial inflow in the ascending colon. AbstractBackground Previous assessments of colon morphology have relied on tests which were either invasive or used ionizing radiation. We aimed to measure regional volumes of the undisturbed colon in healthy volunteers (HV) and patients with diarrhea-predominant irritable bowel syndrome (IBS-D). Methods 3D regional (ascending, transverse, and descending) colon volumes were measured in fasting abdominal magnetic resonance (MR) images of 75 HVs and 25 IBS-D patients. Thirty-five of the HV and all 25 IBS-D subjects were fed a standard meal and postprandial MRI data obtained over 225 min. Key Results Colonic regions were identified and 3D maps from cecum to sigmoid flexure were defined. Fasted regional volumes showed wide variation in both HVs being (mean AE SD) ascending colon (AC) 203 AE 75 mL, transverse (TC) 198 AE 79 mL, and descending (DC) 160 AE 86 mL with no difference from IBS-D subjects (AC 205 AE 69 mL, TC 232 AE 100 mL, and DC 151 AE 71 mL, respectively). The AC volume expanded by 10% after feeding (p = 0.007) in the 35 HV possibly due to increased ileo-colonic inflow. A later rise in AC volume occurred from t = 90 to t = 240 min as the meal residue entered the cecum. In contrast, IBS-D subjects showed a much reduced postprandial response of the AC (p < 0.0001) and a greater increase in TC volume after 90 min (p = 0.0244) compared to HV. Conclusions & Inferences We have defined a normal range of the regional volumes of the undisturbed colon in fasted and fed states. The AC in IBS-D appeared less able to accommodate postprandial inflow which may account for faster colonic transit.

BackgroundFunctional constipation (FC) and irritable bowel syndrome with constipation (IBS‐C) share many symptoms but underlying mechanisms may be different. We have developed a magnetic resonance imaging (MRI) technique to measure intestinal volumes, transit, and motility in response to a laxative, Moviprep®. We aim to use these biomarkers to study the pathophysiology in IBS‐C and FC.MethodsTwenty‐four FC and 24 IBS‐C were studied. Transit was assessed using the weighted average position score (WAPS) of five MRI marker pills, taken 24 h before MRI scanning. Following baseline scan, participants ingested 1 L of Moviprep® followed by hourly scans. Magnetic resonance imaging parameters and bowel symptoms were scored from 0 to 4 h.Key ResultsWeighted average position score for FC was 3.6 (2.5–4.2), significantly greater than IBS‐C at 2.0 (1.5–3.2), p = 0.01, indicating slower transit for FC. Functional constipation showed greater fasting small bowel water content, 83 (63–142) mL vs 39 (15–70) mL in IBS‐C, p < 0.01 and greater ascending colon volume (AC), 314 (101) mL vs 226 (71) mL in IBS‐C, p < 0.01. FC motility index was lower at 0.055 (0.044) compared to IBS‐C, 0.107 (0.070), p < 0.01. Time to first bowel movement following ingestion of Moviprep® was greater for FC, being 295 (116–526) min, compared to IBS‐C at 84 (49–111) min, p < 0.01, and correlated with AC volume 2 h after Moviprep®, r = 0.44, p < 0.01. Using a cut‐off >230 min distinguishes FC from IBS‐C with low sensitivity of 55% but high specificity of 95%.Conclusion & InferencesOur objective MRI biomarkers allow a distinction between FC and IBS‐C.