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Mass Spectrometry Imaging proves differential absorption profiles of well-characterised permeability markers along the crypt-villus axis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
AstraZeneca Gothenburg, Cardiovasc & Metab Dis, Innovat Med & Early Dev, Gothenburg, Sweden..
AstraZeneca Gothenburg, Cardiovasc & Metab Dis, Innovat Med & Early Dev, Gothenburg, Sweden..
AstraZeneca Cambridge, Mass Spectrometry Imaging, Innovat Med & Early Dev, Drug Safety & Metab, Cambridge, England..
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2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 6352Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2017. Vol. 7, article id 6352
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Medical Engineering
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URN: urn:nbn:se:uu:diva-332846DOI: 10.1038/s41598-017-06583-4ISI: 000406273700004PubMedID: 28743866OAI: oai:DiVA.org:uu-332846DiVA, id: diva2:1155651
Funder
Swedish Research Council, 2014-6215Swedish Foundation for Strategic Research , RIF14-0078Science for Life Laboratory - a national resource center for high-throughput molecular bioscience, 452300027AstraZenecaAvailable from: 2017-11-08 Created: 2017-11-08 Last updated: 2017-11-08Bibliographically approved

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