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Intestinal Permeability and Oral Absorption of Selected Drugs Are Reduced in a Mouse Model of Familial Alzheimer's Disease.

ABSTRACT: Compared with the significant number of studies reporting altered abundance and function of drug transporters at the blood-brain barrier (BBB) in Alzheimer's disease (AD), the impact of AD on the abundance of intestinal drug transporters and the subsequent effects on oral drug absorption have received little attention. We have reported the altered abundance of some small intestinal drug transporters in a familial mouse model of AD; however, whether this leads to altered oral drug absorption is unknown. The current study examined plasma concentrations of caffeine and diazepam (markers for transcellular passive transport), digoxin (P-glycoprotein substrate), and valsartan (multidrug resistance-associated protein 2 substrate) following oral administration to 8-10 month old female wild-type (WT) and APPswe/PSEN1dE9 (APP/PS1) transgenic mice, a commonly used mouse model of familial AD. The plasma exposure of valsartan and digoxin was significantly (p < 0.05) lower in APP/PS1 animals compared with WT mice, whereas the plasma concentrations of the passive transcellular markers caffeine and diazepam did not significantly differ between the two genotypes. To assess whether the reduced oral absorption of valsartan and digoxin was due to decreased intestinal transport, the ex vivo transport of the previously mentioned drugs and mannitol (a marker of paracellular transport) across the jejunum of WT and APP/PS1 mice was assessed over 120 min. In line with the in vivo absorption studies, the permeability of caffeine and diazepam did not significantly differ between WT and APP/PS1 mice. The permeability of ³H-digoxin through the APP/PS1 mouse jejunum was lower than that measured through the WT jejunum; the average amount (relative to dose applied) permeating the tissue over 120 min was 0.22 ± 0.11% (mean ± SD) for the APP/PS1 jejunum and 0.85 ± 0.3% for the WT jejunum. A 1.9-fold reduction in the average amount of valsartan permeating the jejunum of APP/PS1 mice relative to that of WT mice was also detected. Although no apparent morphological alterations were observed in the jejunal tissue of APP/PS1 mice, the permeability of ¹⁴C-mannitol across the jejunum from APP/PS1 mice was lower than that across the WT jejunum (P_app= 10.7 ± 3.7 × 10^-6 and 6.0 ± 3.4 × 10^-6 cm/s, respectively), suggesting tightened paracellular junctions in APP/PS1 mice. These studies are the first to demonstrate, in APP/PS1 mice, reduced intestinal permeability and the absorption of drugs commonly prescribed to people with AD for their comorbidities. If these findings translate to people with AD, then modified dosing regimens may be necessary for selected drugs to ensure that their plasma concentrations remain in the effective range.

SUBMITTER: Jin L

PROVIDER: S-EPMC7842083 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: Intestinal morphology and function vary geographically. AIMS: These functions were assessed in asymptomatic volunteers in European, North American, Middle Eastern, Asian, African, and Caribbean countries. METHODS: Five hour urine collections were obtained from each subject following ingestion of a 100 ml iso-osmolar test solution containing 3-0-methyl-D-glucose, D-xylose, L-rhamnose, and lactulose after an overnight fast, to assess active (3-0-methyl-D-glucose) and passive (D-xylose) carrier mediated, and non-mediated (L-rhamnose) absorption capacity, as well as intestinal permeability (lactulose:rhamnose ratio). RESULTS: A comparison of results for subjects from tropical countries (n=218) with those resident in the combined temperate and subtropical region (Europe, United States, Qatar) (n=224) showed significant differences. Residents in tropical areas had a higher mean lactulose:rhamnose ratio and lower mean five hour recoveries of 3-0-methyl-D-glucose, D-xylose, and L-rhamnose, indicating higher intestinal permeability and lower absorptive capacity. Investigation of visiting residents suggested that differences in intestinal permeability and absorptive capacity were related to the area of residence. Subjects from Texas and Qatar, although comprised of several ethnic groups and resident in a subtropical area, showed no significant difference from European subjects. CONCLUSIONS: There are clearly demarcated variations in intestinal permeability and absorptive capacity affecting asymptomatic residents of different geographical areas which correspond with the condition described as tropical enteropathy. Results suggest the importance of environmental factors. The parameters investigated may be relevant to the predisposition of the indigenous population and travellers to diarrhoeal illness and malnutrition. Intestinal function in patients from the tropics may be difficult to interpret, but should take into account the range of values found in the asymptomatic normal population.

Project description:BackgroundUnderstanding the quantitative relationship between a drug's physical chemical properties and its rate of intestinal absorption (QSAR) is critical for selecting candidate drugs. Because of limited experimental human small intestinal permeability data, approximate surrogates such as the fraction absorbed or Caco-2 permeability are used, both of which have limitations.MethodsGiven the blood concentration following an oral and intravenous dose, the time course of intestinal absorption in humans was determined by deconvolution and related to the intestinal permeability by the use of a new 3 parameter model function ("Averaged Model" (AM)). The theoretical validity of this AM model was evaluated by comparing it to the standard diffusion-convection model (DC). This analysis was applied to 90 drugs using previously published data. Only drugs that were administered in oral solution form to fasting subjects were considered so that the rate of gastric emptying was approximately known. All the calculations are carried out using the freely available routine PKQuest Java (http://www.pkquest.com) which has an easy to use, simple interface.ResultsTheoretically, the AM permeability provides an accurate estimate of the intestinal DC permeability for solutes whose absorption ranges from 1% to 99%. The experimental human AM permeabilities determined by deconvolution are similar to those determined by direct human jejunal perfusion. The small intestinal pH varies with position and the results are interpreted in terms of the pH dependent octanol partition. The permeability versus partition relations are presented separately for the uncharged, basic, acidic and charged solutes. The small uncharged solutes caffeine, acetaminophen and antipyrine have very high permeabilities (about 20 x 10-4 cm/sec) corresponding to an unstirred layer of only 45 μm. The weak acid aspirin also has a large AM permeability despite its low octanol partition at pH 7.4, suggesting that it is nearly completely absorbed in the first part of the intestine where the pH is about 5.4.ConclusionsThe AM deconvolution method provides an accurate estimate of the human intestinal permeability. The results for these 90 drugs should provide a useful benchmark for evaluating QSAR models.

Project description:In this work, we studied the intestinal absorption of a peptide with a molecular weight of 4353 Da (MEDI7219) and a protein having a molecular weight of 11 740 Da (PEP12210) in the rat intestinal instillation model and compared their absorption to fluorescein isothiocyanate (FITC)-labeled dextrans of similar molecular weights (4 and 10 kDa). To increase the absorption of the compounds, the permeation enhancer sodium caprate (C10) was included in the liquid formulations at concentrations of 50 and 300 mM. All studied compounds displayed an increased absorption rate and extent when delivered together with 50 mM C10 as compared to control formulations not containing C10. The time period during which the macromolecules maintained an increased permeability through the intestinal epithelium was approximately 20 min for all studied compounds at 50 mM C10. For the formulations containing 300 mM C10, it was noted that the dextrans displayed an increased absorption rate (compared to 50 mM C10), and their absorption continued for at least 60 min. The absorption rate of MEDI7219, on the other hand, was similar at both studied C10 concentrations, but the duration of absorption was extended at the higher enhancer concentration, leading to an increase in the overall extent of absorption. The absorption of PEP12210 was similar in terms of the rate and duration at both studied C10 concentrations. This is likely caused by the instability of this molecule in the intestinal lumen. The degradation decreases the luminal concentrations over time, which in turn limits absorption at time points beyond 20 min. The results from this study show that permeation enhancement effects cannot be extrapolated between different types of macromolecules. Furthermore, to maximize the absorption of a macromolecule delivered together with C10, prolonging the duration of absorption appears to be important. In addition, the macromolecule needs to be stable enough in the intestinal lumen to take advantage of the prolonged absorption time window enabled by the permeation enhancer.

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Intestinal Permeability and Oral Absorption of Selected Drugs Are Reduced in a Mouse Model of Familial Alzheimer's Disease.

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