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Mass Spectrometry Imaging proves differential absorption profiles of well-characterised permeability markers along the crypt-villus axis.

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.

SUBMITTER: Nilsson A

PROVIDER: S-EPMC5526999 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:At various postnatal stages, intestinal epithelial cells were isolated sequentially from villus tip to crypt base by successive EDTA treatments. According to the localization of marker enzymic activities, isolated cells were pooled into three cell compartments: villus (V), lower villus and upper crypt (VC) and crypt (C). Purified brush-border-membrane proteins were separated by 7.5%-polyacrylamide-gel electrophoresis in the presence of sodium dodecyl sulphate. Enzymic activities could be assigned to some protein bands: maltase/glucoamylase (protein band 3), sucrase-isomaltase (protein bands 3 and 6), lactase (protein band 5) and alkaline phosphatase (region of protein bands 8 and 9). The findings suggest the following. (1) Sucrase-isomaltase activities appeared in compartment C at 17 days with a simultaneous increase of the pre-existing protein band 3 and appearance of a well-defined protein band in position 6; the enzymic complex remained still present in the crypt cells until adulthood. From the day 21 onwards, sucrase-isomaltase was detected in compartments VC and V. (2) Lactase was only present in the three cell compartments until day 21; at this developmental stage its activity completely disappeared from compartment C, in spite of the persistence of a weak protein band. (3) Alkaline phosphatase activity could be detected as a single peak corresponding to protein band 9 in all three cell compartments until day 21; thereafter it was replaced by two peaks of activity showing a less precise correlation with the well-defined protein bands 8 and 9. In the crypt cells of the adult rat, however, the preweaning situation, which was regularly observed, is an unexpected phenomenon. (4) Maltase and glucoamylase did not display any marked qualitative or quantitative modifications either along the villus-crypt axis or during the period of postnatal development studied. Evidence is given from the present data that each brush-border enzyme investigated has a specific developmental pattern.

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Mass Spectrometry Imaging proves differential absorption profiles of well-characterised permeability markers along the crypt-villus axis.

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