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Comparison and Prediction of Inhibitors of the Three Major Human ATP-Binding Cassette Transporters P-gp, BCRP and MRP2
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
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Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-96584OAI: oai:DiVA.org:uu-96584DiVA: diva2:171209
Available from: 2007-12-20 Created: 2007-12-20 Last updated: 2010-01-13Bibliographically approved
In thesis
1. ATP-Binding Cassette Efflux Transporters and Passive Membrane Permeability in Drug Absorption and Disposition
Open this publication in new window or tab >>ATP-Binding Cassette Efflux Transporters and Passive Membrane Permeability in Drug Absorption and Disposition
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Transport into and across the cells of the human body is a prerequisite for the pharmacological action of drugs. Passive membrane permeability and active transport mechanisms are major determinants of the intestinal absorption of drugs, as well as of the distribution to target tissues and the subsequent metabolism and excretion from the body. In this thesis, the role of ATP-binding cassette (ABC) transporters and passive permeability on drug absorption and disposition was investigated. Particular emphasis was placed on defining the molecular properties important for these transport mechanisms.

The influence of different transport pathways on predictions of intestinal drug absorption was investigated using experimental models of different complexity. Experimental models that include the paracellular pathway gave improved predictions of intestinal drug absorption, especially for incompletely absorbed drugs. Further, the inhibition of the ABC transporters breast cancer resistance protein (BCRP/ABCG2) and multidrug-resistance associated protein 2 (MRP2/ABCC2) was experimentally investigated using structurally diverse datasets that were representative of orally administered drugs. A large number of previously unknown inhibitors were identified among registered drugs, but their clinical relevance for drug-drug interactions and drug-induced toxicity remains to be determined. The majority of the inhibitors affected all three major ABC transporters BCRP, MRP2 and P-glycoprotein (P gp/ABCB1), and these multi-specific inhibitors were found to be enriched in highly lipophilic weak bases.

To summarize, the present work has led to an increased knowledge of the molecular features of importance for ABC transporter inhibition and passive membrane permeability. Previously unknown ABC transporter inhibitors were identified and predictive computational models were developed for the different drug transport mechanisms. These could be valuable tools to assist in the prioritization of experimental efforts in early drug discovery.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 68 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 67
Pharmaceutics, ATP-binding cassette, ABC transporter, P-gp, P-glycoprotein, ABCB1, BCRP, Breast cancer resistance protein, ABCG2, MRP2, Multidrug-resistance associated protein 2, ABCC2, Membrane permeability, Drug transport, Active transport, Passive diffusion, Multivariate data analysis, PLS, OPLS, QSAR, Galenisk farmaci
urn:nbn:se:uu:diva-8371 (URN)978-91-554-7058-6 (ISBN)
Public defence
2008-01-18, B21, Uppsala Biomedicinska Centrum BMC, Husargatan 3, Uppsala, 09:15
Available from: 2007-12-20 Created: 2007-12-20Bibliographically approved

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