Magnetic Resonance Imaging Quantification of Fasted State Colonic Liquid Pockets in Healthy Humans

Abstract

The rate and extent of drug dissolution and absorption from solid oral dosage forms is highly dependent on the volume of liquid in the gastrointestinal tract (GIT). However, little is known about the time course of GIT liquid volumes after drinking a glass of water (8 oz), particularly in the colon, which is a targeted site for both locally and systemically acting drug products. Previous magnetic resonance imaging (MRI) studies offered novel insights on GIT liquid distribution in fasted humans in the stomach and small intestine, and showed that freely mobile liquid in the intestine collects in fairly distinct regions or "pockets". Based on this previous pilot data, we hypothesized that (1) it is possible to quantify the time course of the volume and number of liquid pockets in the undisturbed colon of fasted healthy humans following ingestion of 240 mL, using noninvasive MRI methods; (2) the amount of freely mobile water in the fasted human colon is of the order of only a few milliliters. Twelve healthy volunteers fasted overnight and underwent fasted abdominal MRI scans before drinking 240 mL (∼8 fluid ounces) of water. After ingesting the water they were scanned at frequent intervals for 2 h. The images were processed to quantify freely mobile water in the total and regional colon: ascending, transverse, and descending. The fasted colon contained (mean ± SEM) 11 ± 5 pockets of resting liquid with a total volume of 2 ± 1 mL (average). The colonic fluid peaked at 7 ± 4 mL 30 min after the water drink. This peak fluid was distributed in 17 ± 7 separate liquid pockets in the colon. The regional analysis showed that pockets of free fluid were found primarily in the ascending colon. The interindividual variability was very high; the subjects showed a range of number of colonic fluid pockets from 0 to 89 and total colonic freely mobile fluid volume from 0 to 49 mL. This is the first study measuring the time course of the number, regional location, and volume of pockets of freely mobile liquid in the undisturbed colon of fasted humans after ingestion of a glass of water. Novel insights into the colonic fluid environment will be particularly relevant to improve our understanding and design of the in vivo performance of controlled release formulations targeted to the colon. The in vivo quantitative information presented here can be input into physiologically based mechanistic models of dissolution and absorption, and can be used in the design and set up of novel in vitro performance tools predictive of the in vivo environment.

Insights Into the Different Effects of Food on Intestinal Secretion Using Magnetic Resonance Imaging

“…This was a pilot study because no data are available on the effect of ingested lettuce or rhubarb on MRI parameters. However, using n = 16, we had previously detected significant differences in SBWC induced by the mild laxative bran that were less than the changes anticipated in this study.…”

“…This is measured in the same way as the SBWC and reflects only freely mobile water with long transverse relaxation time and is only a small fraction of the total water. 7 We therefore also measured ascending colon longitudinal relaxation time (T1AC; in milliseconds), which in this context can provide a more useful assessment of colonic contents. T1 is a fundamental MRI parameter that reflects the time constant for the water hydrogen protons to return to their equilibrium state following a radiofrequency excitation pulse.…”

“…Secondary MRI outcomes included ascending colon water content (ACWC; in mL). This is measured in the same way as the SBWC and reflects only freely mobile water with long transverse relaxation time and is only a small fraction of the total water . We therefore also measured ascending colon longitudinal relaxation time (T1AC; in milliseconds), which in this context can provide a more useful assessment of colonic contents.…”

Low‐FODMAP Diet Is Associated With Improved Quality of Life in IBS Patients—A Prospective Observational Study

“…The efficacy of low‐FODMAP diet in improving GI symptoms in people with IBS has been demonstrated in a range of retrospective, prospective, uncontrolled, and controlled studies from multiple centers around the world . In addition to clinical efficacy, there has been increasing work demonstrating the mechanisms of action, including microbiological, MRI, breath test, and metabolite studies . While the mechanism of action for the effect of low‐FODMAP diet on gastroenterological symptoms becomes clearer, it is worthwhile to consider secondary benefits from improving GI symptoms in people with IBS.…”

Mechanistic Study of Belinostat Oral Absorption From Spray-Dried Dispersions

“…[37][38][39][40] Dose concentrations (1 mg/mL in the stomach and 0.5 mg/mL in the intestine) were chosen based on average gastric and intestinal volumes in dogs and an estimate of the rate-determining steps to absorption in the intestinal compartment. 37,41,42 The SGF portion of the SGF/SIF dissolution test represented a nonsink condition for all SDDs, whereas the SIF portion of the test represented near-sink conditions, with a potential for up to 40% of the saturation solubility reached for HPMCAS-M and PVP K30 SDDs and 100% saturation solubility reached for the PVP VA64 SDD (based on data from the solventshift UV assay, Table 2). Sink conditions in the SIF portion of the dissolution test are consistent with the estimation of dissolutionrate-limited performance of these SDDs in the upper small intestine of fasted dogs according to the Fraction Absorbed Classification System.…”