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Comprehensive study on regional human intestinal permeability and prediction of fraction absorbed of drugs using the Ussing chamber technique
Global In Silico & In Vitro DMPK, AstraZeneca R&D, Mölndal, Sweden.
CVGI iMED DMPK AstraZeneca R&D, Mölndal, Sweden.
Medicines Evaluation, Pharmaceutical Development, AstraZeneca R&D, Mölndal, Sweden.
Medicines Evaluation, Pharmaceutical Development, AstraZeneca R&D, Mölndal, Sweden.
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2013 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 48, no 1-2, 166-180 p.Article in journal (Refereed) Published
Abstract [en]

The purpose of this study was to evaluate the use of human intestinal tissue in Ussing chamber to predict oral and colonic drug absorption and intestinal metabolism. Data on viability, correlation between apparent permeability coefficients (Papp) and fraction absorbed (fa) after oral and colonic administration, regional permeability, active uptake and efflux of drugs as well as intestinal metabolism were compiled from experiments using 159 human donors. Permeability coefficients for up to 28 drugs were determined using one or several of four intestinal regions: duodenum, jejunum, ileum and colon and 10 drugs were studied bidirectionally. Viability was monitored simultaneously with transport experiments by recording potential difference (PD), short-circuit current (SCC) and the resistance (TER). Intestinal metabolism was studied using testosterone and midazolam as probe substrates.

There was a steep sigmoidal correlation between Papp in the Ussing chamber, using jejunal segments, and oral fa in humans, for a set of 25 drugs (R2: 0.85, p < 0.01). A clear sigmoidal relationship was also obtained between Papp in colonic segments and fa after colonic administration in humans for a set of 10 drugs (R2: 0.93, p < 0.05). Regional permeability data showed a tendency for highly permeable compounds to have higher or similar Papp in colon as in the small intestinal segments, while the colonic regions showed a lower Papp for more polar compounds as well as for d-glucose and l-leucine. Bidirectional transport (mucosa to serosa and serosa to mucosa direction) in jejunum showed well functioning efflux- and uptake asymmetry. Intestinal metabolic extraction during transport across jejunum segments was found for both testosterone and midazolam.

In conclusion, viable excised human intestine mounted in the Ussing chamber, is a powerful technique for predicting regional fraction absorbed (fa), transporter-mediated uptake or efflux as well as intestinal metabolism of drug candidates in man. Furthermore, a sigmoidal relationship of Papp vs. fa was obtained when permeability data from the present study were merged with data from 2 other independent laboratories (R2: 0.83, p < 0.01). The correlation curve reported can be used by any laboratory for predictions of human permeability and fa. In addition, for the first time a correlation curve between colonic Papp and human colonic fa is reported, which demonstrates the usefulness of this methodology in early assessment of the colonic absorption potential of extended release formulation candidates. © 2012 Elsevier B.V. All rights reserved.

Place, publisher, year, edition, pages
Amsterdam: Elsevier B.V , 2013. Vol. 48, no 1-2, 166-180 p.
Keyword [en]
Ussing chamber, Human intestine, Absorption, Intestinal permeability, Regional permeability, Intestinal metabolism
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:hh:diva-24117DOI: 10.1016/j.ejps.2012.10.007ISI: 000315613500019PubMedID: 23103351Scopus ID: 2-s2.0-84870163047OAI: oai:DiVA.org:hh-24117DiVA: diva2:679515
Available from: 2013-12-16 Created: 2013-12-09 Last updated: 2015-03-03Bibliographically approved

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CiteExportLink to record
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