Intestinal fluid volumes and transit of dosage forms as assessed by magnetic resonance imaging

Abstract

SUMMARYAim: The gastrointestinal transit of sequentially administered capsules was investigated in relation to the availability of fluid along the intestinal lumen by magnetic resonance imaging. Methods: Water-sensitive magnetic resonance imaging was performed on 12 healthy subjects during fasting and 1 h after a meal. Specifiable non-disintegrating capsules were administered at 7, 4 and 1 h prior to imaging. Results: While food intake reduced the mean fluid volumes in the small intestine (105 ± 72 mL vs. 54 ± 41 mL, P < 0.01) it had no significant effect on the mean fluid volumes in the colon (13 ± 12 mL vs. 18 ± 26 mL). The mean number of separated fluid pockets increased in both organs after meal (small intestine: 4 vs. 6, P < 0.05; large intestine: 4 vs. 6, P < 0.05). The distribution of capsules between the small and large intestine was strongly influenced by food (colon: 3 vs. 17 capsules, P < 0.01). Conclusions:The results show that fluid is not homogeneously distributed along the gut, which likely contributes to the individual variability of drug absorption. Furthermore, transport of fluid and solids through the ileocaecal valve is obviously initiated by a meal-induced gastro-ileocaecal reflex.

Investigating the effect of solubility and density gradients on local hydrodynamics and drug dissolution in the USP 4 dissolution apparatus

“…The results indicate that the dissolution rate during a short time frame at locations near the dissolving surface may be more complex than regular effluent measurements would suggest. This is of relevance for situations where a dissolving surface may encounter non-sink conditions, for example during certain phases of its journey 575 through the gastro-intestinal tract, where it may encounter low fluid volumes (Schiller et al, 2005). Furthermore, the results suggest that a freely soluble excipient, such as LM, may affect the Page 27 of 40 A c c e p t e d M a n u s c r i p t 25 local hydrodynamic environment during dissolution testing of a low solubility active ingredient.…”

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

“…[6,7,212] The fluid volume in the small intestine is however not constant, for example it has been shown that it decreases by approximately 50% in fed vs fasted state. [215] On the other hand, many drug substances have poor solubility and/or low dissolution rate which means that the intestinal drug concentration may be overestimated. Other definitions for the intestinal drug concentration have been proposed by the FDA and EMA in their guidances on bioavailability and bioequivalence when classifying drug compounds into the biopharmaceutics classification system (BCS).…”

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

“…This work has been extended to the small bowel environment. MRI showed that liquid in the small bowel is present in discrete liquid "pockets" (Schiller et al, 2005); these have been quantified under conditions representing bioavailability/bioequivalence (BA/BE) studies at fasted baseline and after a 240 ml glass of water, using methods validated against naso-duodenal infusion (Hoad et al, 2007). The method is based on a heavily T2 (i.e.…”

“…This has been done using 'transit capsule markers' filled with MRI-visible fluid. The imaging was based either on standard 1 H MRI Schiller et al, 2005) but also on 19 F MRI (Hahn et al, 2011(Hahn et al, , 2012(Hahn et al, , 2014, an interesting approach though the availability of the necessary hardware is scarce. The position of the MRI markers can be visualized and transit determined in a fashion similar to the radiological methods .…”