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Transport mechanisms of fexofenadine in jejunum, ileum and colon: experiences from a novel in vivo intubation approach
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
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Article in journal (Refereed) Submitted
URN: urn:nbn:se:uu:diva-93089OAI: oai:DiVA.org:uu-93089DiVA: diva2:166460
Available from: 2005-04-29 Created: 2005-04-29Bibliographically approved
In thesis
1. Involvement of Membrane Transport Proteins in Intestinal Absorption and Hepatic Disposition of Drugs Using Fexofenadine as a Model Drug
Open this publication in new window or tab >>Involvement of Membrane Transport Proteins in Intestinal Absorption and Hepatic Disposition of Drugs Using Fexofenadine as a Model Drug
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The aims of this thesis were to study the in vivo relevance of membrane transporters for intestinal absorption and the hepatic disposition of drugs in humans and preclinical models. Fexofenadine is a substrate for ABCB1 (P-glycoprotein) and members of the organic anion transporting polypeptide (OATP/SLCO) family. It is marginally metabolised in humans.

The influence of known inhibitors of ABCB1 and OATPs on the membrane transport and pharmacokinetics of fexofenadine was investigated in Caco-2 and porcine models and in humans. The permeability of fexofenadine remained low, even when significantly altered by the addition of an inhibitor. Using the Loc-I-Gut® technique in vivo in humans, it was possible to see that the jejunal effective permeability of fexofenadine was unchanged when given with verapamil. However, the systemic exposure and apparent absorption rate of fexofenadine increased. This suggests that the first-pass liver extraction of fexofenadine was reduced by verapamil, probably through the inhibition of sinusoidal OATP-mediated and/or canalicular ABCB1-mediated secretion. The unchanged permeability can be explained by simultaneous inhibition of jejunal apical OATP-uptake and ABCB1-efflux, which would leave fexofenadine to be transported by passive trancellular diffusion. A Loc-I-Gut® perfusion in the porcine model enabling blood sampling in the portal and hepatic veins and bile collection revealed increased jejunal permeability, but no subsequent verapamil-induced elevation in the systemic exposure of fexofenadine. This indicates a species-related difference in the localisation of and/or the substrate specificity of fexofenadine for the transporters involved. The absence of an effect on the first-pass liver extraction in the porcine model might be caused by the observed lower liver exposure of verapamil.

Finally, a novel intubation technique enabling dosing of fexofenadine in the jejunum, ileum and the colon showed that fexofenadine was absorbed less along the length the intestine in agreement with the properties of a low permeability drug.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 62 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 13
Biopharmacy, Fexofenadine, OATP, P-glycoprotein, Organic Anion Transporters, ATP-Binding Cassette Transporters, membrane transport proteins, Bioavailability, Biopharmaceutics, Biofarmaci
National Category
Pharmaceutical Sciences
urn:nbn:se:uu:diva-5808 (URN)91-554-6257-X (ISBN)
Public defence
2005-05-21, B 21, Uppsala biomedicinska centrum (BMC), Husargatan 3, Uppsala, 09:15
Available from: 2005-04-29 Created: 2005-04-29 Last updated: 2014-01-27Bibliographically approved

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