Characterizing interregional differences in the rheological properties and composition of rat small intestinal mucus.

The mucus layer in the small intestine is generally regarded as a barrier to drug absorption. However, the mucus layer is a complex system, and presently, only a few studies have been conducted to elucidate its physicochemical properties. The current study hypothesizes that the mucus layer contains solubility-enhancing surfactants and thus might aid the oral absorption of poorly water-soluble drugs. Mucus was sampled from sections of the small intestine of fasted rats to analyze the rheological properties and determine the mucus pH and concentrations of proteins and endogenous surfactants, i.e., bile salts, polar lipids, and neutral lipids. The mucus layer in the two proximal sections of the small intestine exhibited different rheological properties such as higher zero-shear viscosity and lower loss tangent and higher protein concentrations compared to all subsequent sections of the small intestine. The pH of the mucus layer was stable at ~ 6.5 throughout most of the small intestine, but increased to 7.5 in the ileum. The bile salt concentrations increased from the duodenum (16.0 ± 2.2 mM) until the mid jejunum (55.1 ± 9.5 mM), whereas the concentrations of polar lipids and neutral lipids decreased from the duodenum (17.4 ± 2.2 mM and 37.8 ± 1.6 mM, respectively) until the ileum (4.8 ± 0.4 mM and 10.7 ± 1.1 mM, respectively). In conclusion, the mucus layer of the rat small intestine contains endogenous surfactants at levels that might benefit solubilization and absorption of orally administered poorly water-soluble drugs.

Assessing acute colitis induced by dextran sulfate sodium in rats and its impact on gastrointestinal fluids.

Dextran sulfate sodium (DSS) is commonly used to induce colitis in rats. While the DSS-induced colitis rat model can be used to test new oral drug formulations for the treatment of inflammatory bowel disease, the effect of the DSS treatment on the gastrointestinal tract has not been thoroughly characterized. Additionally, the use of different markers to assess and confirm successful induction of colitis is somewhat inconsistent. This study aimed to investigate the DSS model to improve the preclinical evaluation of new oral drug formulations. The induction of colitis was evaluated based on the disease activity index (DAI) score, colon length, histological tissue evaluation, spleen weight, plasma C-reactive protein, and plasma lipocalin-2. Furthermore, the study investigated how the DSS-induced colitis affected the luminal pH, lipase activity, and concentrations of bile salts, polar lipids, and neutral lipids. For all evaluated parameters, healthy rats were used as a reference. The DAI score, colon length, and histological evaluation of the colon were effective disease indicators in DSS-induced colitis rats, while spleen weight, plasma C-reactive protein, and plasma lipocalin-2 were not. The luminal pH of the colon and bile salt- and neutral lipid concentrations in regions of the small intestine were lower in DSS-induced rats compared to healthy rats. Overall, the colitis model was deemed relevant for investigating ulcerative colitis-specific formulations.

Impact of oral gavage technique of drug-containing microcontainers on the gastrointestinal transit and absorption in rats.

Oral gavage is the most common way to administer drug formulations orally to rats. Yet, the technique applied and its influence on gastrointestinal (GI) transit receive little attention. This study aims to investigate the impact of three oral gavage techniques on GI transit and drug absorption utilizing microcontainers (MCs). The MCs were filled with paracetamol and BaSO4 (1:1 w/w ratio), coated with Eudragit S100, and filled into size-9 gelatin capsules. An in vitro study confirmed the intactness of the coating, and the capsules were administered to rats with air, water, or a piston. X-ray imaging determined the locations of the MCs, and the corresponding plasma concentration of paracetamol established a correlation with the location. The fastest GI transit occurred with air-dosing, while water-dosing caused delayed gastric emptying for 3 h with non-quantifiable paracetamol absorption. Piston-dosed MCs were retained in the stomach for up to 1 h, though for 3 h in one rat. Air-dosing caused discomfort and stress in rats, thus limiting its ethical and physiological relevance. Water-dosing confined its use due to delayed gastric emptying. In conclusion, the oral gavage technique affected the GI transit of MCs and, consequently, drug absorption. Piston-dosing appeared to be the superior dosing technique.

X-ray Imaging for Gastrointestinal Tracking of Microscale Oral Drug Delivery Devices.

Microscale devices are promising tools to overcome specific challenges within oral drug delivery. Despite the availability of advanced high-quality imaging techniques, visualization and tracking of microscale devices in the gastrointestinal (GI) tract is still a challenge. This work explores the possibilities of applying planar X-ray imaging and computed tomography (CT) scanning for visualization and tracking of microscale devices in the GI tract of rats. Microcontainers (MCs) are an example of microscale devices that have shown great potential as an oral drug delivery system. Barium sulfate (BaSO4) loaded into the cavity of the MCs increases their overall X-ray contrast, which allows them to be easily tracked. The BaSO4-loaded MCs are quantitatively tracked throughout the entire GI tract of rats by planar X-ray imaging and visualized in 3D by CT scanning. The majority of the BaSO4-loaded MCs are observed to retain in the stomach for 0.5-2 h, enter the cecum after 3-4 h, and leave the cecum and colon 8-10 h post-administration. The imaging approaches can be adopted and used with other types of microscale devices when investigating GI behavior in, for example, preclinical trials and potential clinical studies.

Assessment of the analgesic dipyrone as a possible (anti)androgenic endocrine disruptor.

Mild analgesics have been associated with antiandrogenic effects, but there are no such studies on dipyrone, despite its high prevalence of use in many countries. We examined the production of steroid hormones in human H295R cells after exposure to dipyrone and two metabolites, 4-Methylaminoantipyrine (MAA) and 4-Aminoantipyrine (AA), as well as fetal testicular testosterone production in rats following maternal dipyrone exposure. Androgen agonistic/antagonistic effects were examined in vitro for dipyrone and its metabolites in the Yeast Androgen Screen (YAS) assay and in vivo for dipyrone through the Hershberger assay. In vitro we tested dipyrone, MAA, and AA (0.1-1000 µM) while in vivo we used dipyrone (50, 100, 200 mg/kg/day). In the H295R assay, dipyrone, MAA and AA reduced the production of androgens and corticosteroids. Testosterone was reduced at concentrations 4-13 times higher than the maximum plasma concentrations reported in humans for MAA and AA. No effects were observed in the fetal testosterone production assay. In the YAS and Hershberger assays, no androgen agonistic/antagonistic activities were observed. These results indicate that dipyrone and its metabolites do not interact with the androgen receptor, but have the potential to inhibit steroidogenesis, however only at concentrations that are not relevant under normal medical use.