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Regional Intestinal Permeability in Rats: A Comparison of Methods
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0002-1525-1430
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0002-5586-2906
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.ORCID iD: 0000-0003-4318-6039
AstraZeneca R&D, Pharmaceut Technol & Dev, S-43183 Gothenburg, Sweden..
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2017 (English)In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 14, no 12, p. 4252-4261Article in journal (Refereed) Published
Abstract [en]

Currently, the screening of new drug candidates for intestinal permeation is typically based on in vitro models which give no information regarding regional differences along the gut. When evaluation of intestinal permeability by region is undertaken, two preclinical rat models are commonly used, the Ussing chamber method and single-pass intestinal perfusion (SPIP). To investigate the robustness of in vivo predictions of human intestinal permeability, a set of four model compounds was systematically investigated in both these models, using tissue specimens and segments from the jejunum, ileum, and colon of rats from the same genetic strain. The influence of luminal pH was also determined at two pH levels. Ketoprofen had high and enalaprilat had low effective (P-eff) and apparent (P-app) permeability in all three regions and at both pH levels. Metoprolol had high P-eff in all regions and at both pHs and high P-app at both pHs and in all regions except the jejunum, where P-app was low. Atenolol had low P-eff in all regions and at both pHs, but had high P-app at pH 6.5 and low P-app at pH 7.4. There were good correlations between these rat in situ P-eff (SPIP) and human in vivo P-eff determined previously for the same compounds by both intestinal perfusion of the jejunum and regional intestinal dosing. The results of this study indicate that both investigated models are suitable for determining the regional permeability of the intestine; however, the SPIP model seems to be the more robust and accurate regional permeability model.

Place, publisher, year, edition, pages
2017. Vol. 14, no 12, p. 4252-4261
Keywords [en]
intestinal permeability, Ussing chamber method, single-pass intestinal perfusion, jejunum, ileum, colon, rat
National Category
Pharmacology and Toxicology
Identifiers
URN: urn:nbn:se:uu:diva-345176DOI: 10.1021/acs.molpharmaceut.7b00279ISI: 000417342400014PubMedID: 28920690OAI: oai:DiVA.org:uu-345176DiVA, id: diva2:1188757
Funder
EU, FP7, Seventh Framework Programme, FP7/2007-013Available from: 2018-03-08 Created: 2018-03-08 Last updated: 2018-03-08Bibliographically approved

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Roos, CarlDahlgren, DavidSjögren, ErikLennernäs, Hans

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