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Knowledge of the fate of an orally administered drug in the gastrointestinal tract may be of crucial importance for the development of drugs. For example, orally administered enzyme preparations aiming to improve fat digestion, and consequently to control steatorrhoea in chronic exocrine pancreatic insufficiency, are often not distributed homogeneously within the gastric contents. Therefore, they do not empty simultaneously with the food into the small intestine, diminishing their efficacy to improve maldigestion.1–3
Among the various techniques used to study the release and distribution of orally administered drugs in vivo, scintigraphy has been most successful in visualizing the fate of pharmaceutical dosage forms in the gastrointestinal tract.4, 5 However, when a detailed knowledge of the location of drug–food interactions or of the properties of complex release systems is sought, the two-dimensional nature of scintigraphy imposes limitations that can be overcome by the three-dimensional capabilities of magnetic resonance imaging (MRI). We recently used MRI to follow the intragastric release of a colloidal drug model containing gadolinium tetra-azacyclododecane tetra-acetic acid (Gd-DOTA) from a gelatine capsule in the food-filled human stomach.6 We observed that the distribution of the drug model in the stomach (i.e. within the meal) was dependent on the composition and consistency of the meal. The drug model appeared to distribute predominantly in the accessible liquid compartment of the meal. Our data also suggested that the degree of homogeneity of the drug model distribution in the stomach may influence the time course of drug release into the small intestine (i.e. gastric emptying).
The first aim of this study was to investigate the effects of test meals of different consistencies and containing different amounts of liquid ingested with the meal on the intragastric distribution of a contrast marker. This was achieved by administering a gelatine capsule containing Gd-DOTA solution, an MRI contrast agent, and visualizing its release from the capsule after ingestion of meals of different composition. The second aim was to demonstrate the three-dimensional capabilities of MRI in clarifying the distribution processes in the stomach. We hypothesized that the intragastric distribution of a marker will be related to the amount of accessible liquid contained in the meal, and that the consistency of the meal will affect the spatial distribution of the contrast marker in the stomach, resulting in large differences in the timing of its delivery to the small intestine.
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In this study, we have shown that meal consistency can strongly affect the intragastric distribution of a contrast marker after the ingestion of meals with similar gastric emptying rates. On the other hand, the amount of liquid ingested with the meal has only a small effect on intragastric marker distribution.
We observed significant differences in contrast marker distribution between meals A (homogeneous) and B (particulate). Generally, in the antrum, meal and contrast marker were mixed more homogeneously, while a large part of the meal in the fundus was not accessible to the marker. This may indicate that, under certain circumstances, a drug may be emptied from the stomach before the meal, even when the capsule is ingested after the food, or when given in a liquid form. The differences in intragastric marker distribution between the rice (particulate) and mashed potato (homogeneous) meals may perhaps be explained by the different meal consistencies. The particulate nature of the rice meal made the meal more easily accessible to the liquid, while the mashed potato meal, with its denser consistency, could only be infiltrated by liquid, and hence the marker, to a limited extent. This interpretation is also in line with our hypothesis that the intragastric distribution of a contrast marker is related to the accessible liquid volume.6 We tested this hypothesis further by administering to our subjects two meals that varied only in the amounts of water ingested. Accordingly, the contrast marker should have distributed in a larger volume in meal D, containing 200 mL more water than meal C. However, the distribution volumes did not differ between the two meals. One explanation may be the rapid gastric emptying rate of non-nutrient liquid,8 preventing a homogeneous distribution of the marker in the liquid phase over the course of the study. A nutrient-containing drink, as used in our previous study,6 may have provided different results, as it is emptied from the stomach more slowly and may therefore allow more time for the distribution process to occur.
For all meals, the contrast marker showed a preferential distribution from the fundus along the inner curvature of the stomach wall into the antrum. Consequently, a large proportion of the fundic content did not come into contact with the marker. According to our results, it is likely that the marker bypassed a large part of the meal, in particular in the fundus, and was emptied from the stomach before any significant mixing with the meal had taken place.
Our data show that MRI is a valuable technique to study the behaviour of oral dosage forms, as three-dimensional gastric images can be reconstructed and important parameters, such as gastric emptying and motility, can be monitored.6, 9, 10 It is important to note that our studies have focused on the assessment of the intragastric distribution of the marker rather than on small intestinal exposure to the marker. As our calculations of marker concentrations are based on measured intensities, very small concentrations, such as those emptied into the small intestine, may, at this stage, fall below the detection limit. Also, MRI allows the performance of repeated studies in healthy subjects, as it does not involve exposure to ionizing radiation. A variety of techniques have been used previously to study the fate of pharmaceutical dosage forms. The most commonly used method for in vivo imaging to date has been γ-scintigraphy.4 Dual-isotope imaging techniques allow the labelling of the drug and meal, and thus the assessment of drug distribution relative to the meal.3, 11 This is an advantage over MRI, where direct labelling of the drugs with an MRI marker has so far not been approved for clinical studies. Significant limitations of γ-scintigraphy include the restriction to two dimensions and the exposure to ionizing radiation. As alternative methods, gastrointestinal magnetomarkergraphy and a superconducting quantum interference device (SQUID) have been proposed to study transit times through the gastrointestinal tract.12, 13 However, studies utilizing these methods only focus on the location of solid, non-disintegrating capsules and do not provide information on the release of a dosage form.
Our data indicate that meals with a similar energy content empty from the stomach at similar rates regardless of their composition and consistency. Meals with a more particulate consistency (rice, hamburger meal) probably mixed reasonably well with gastric secretions and ingested liquid, were ground and then emptied. The homogeneous meal (mashed potato) did not require trituration, but emptied from the stomach at a similar rate. This may be due to the denser consistency of this meal, resulting in a longer period of time for gastric secretions to penetrate and liquefy this meal. The results are in agreement with earlier studies showing that meal consistency only has a modest influence on gastric emptying.14, 15
In summary, our data show that meal consistency has a significant impact on the intragastric distribution of a contrast marker, even at similar gastric emptying rates of the meals. Furthermore, our data indicate that non-nutrient fluid ingested with the meal does not appear to increase the intragastric distribution of the marker. We also demonstrated that MRI can simultaneously visualize the distribution kinetics of the marker in relation to gastric anatomy in three dimensions and at high resolution. This technique will therefore be of great value for optimizing the behaviour of new dosage forms and for the analysis and clarification of basic distribution mechanisms in the stomach.