Abstract
Knowledge about the region-specific absorption profiles from the gastrointestinal tract of orally administered drugs is a critical factor guiding dosage form selection in drug development. We have used a novel approach to study three well-characterized permeability and absorption marker drugs in the intestine. Propranolol and metoprolol (highly permeable compounds) and atenolol (low-moderate permeability compound) were orally co-administered to rats. The site of drug absorption was revealed by high spatial resolution matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) and complemented by quantitative measurement of drug concentration in tissue homogenates. MALDI-MSI identified endogenous molecular markers that illustrated the villi structures and confirmed the different absorption sites assigned to histological landmarks for the three drugs. Propranolol and metoprolol showed a rapid absorption and shorter transit distance in contrast to atenolol, which was absorbed more slowly from more distal sites. This study provides novel insights into site specific absorption for each of the compounds along the crypt-villus axis, as well as confirming a proximal-distal absorption gradient along the intestine. The combined analytical approach allowed the quantification and spatial resolution of drug distribution in the intestine and provided experimental evidence for the suggested absorption behaviour of low and highly permeable compounds.
Highlights
During the development of new therapeutics it is important to build an understanding of the parameters that influence absorption
The in vitro method of choice for determining permeability and predicting oral absorption behaviour is the Caco-2 cell monolayer assay. This model is based on a single cell type of columnar epithelial absorptive cells, typically grown on flat monolayer sheets, and as such does not permit studies that investigate the impact of different cell types in the intestine, e.g. mucus-producing goblet cells, or the intestinal structure itself[15, 16]
Describing compound distribution across the villi of a rat intestine by MALDI-MSI requires an experimental set up where the tissue fixation, MALDI matrix crystal size and the spatial resolution are optimized to enable the fine anatomical features, like the villi structure, to be spatially resolved
Summary
During the development of new therapeutics it is important to build an understanding of the parameters that influence absorption. Atenolol 266.34 −1.51 0.20 Base dimensions of the site of absorption, longitudinally from duodenum to colon, and vertically from villi tips to crypts, is an important element enabling the prediction of the right dose and the right dosing regimen, and opens up the possibility for directing drugs to specific targets in the intestinal structure, such as an individual cell type along the crypt villus axis. The aim of this study was to use the high spatial resolution of MALDI-MSI to study differential drug diffusion along the crypt-villus axis as well as longitudinal absorption from proximal to distal small intestine in rats. In addition to the proximal-distal absorption measurements, high spatial resolution MALDI-MSI demonstrated that it was possible to relatively quantify and resolve the drug distribution in the intestinal mucosa and to measure the drugs’ vertical absorption profiles over and along the height of the villi
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