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Association between the number of coadministered P-glycoprotein inhibitors and serum digoxin levels in patients on therapeutic drug monitoring
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
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2004 In: BMC Medicine, 2-8 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2004. 2-8 p.
URN: urn:nbn:se:uu:diva-93728OAI: oai:DiVA.org:uu-93728DiVA: diva2:167298
Available from: 2005-11-17 Created: 2005-11-17Bibliographically approved
In thesis
1. Interindividual Variability of Drug Transport Proteins: Focus on Intestinal Pgp (ABCB1) and BCRP (ABCG2)
Open this publication in new window or tab >>Interindividual Variability of Drug Transport Proteins: Focus on Intestinal Pgp (ABCB1) and BCRP (ABCG2)
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The appearance of adverse drug reactions is a common reason for hospitalization in Western countries. Research on underlying biological mechanisms for interindividual variability in drug response aims to better identify patients with exceptional genetic traits, disease conditions or risk of drug-drug interactions and thereby help to prevent adverse drug reactions.

Active transport mechanisms are involved in the absorption and disposition of several therapeutic agents. The main objective of this thesis was to investigate factors potentially affecting transport proteins and thus contributing to variability in drug absorption and disposition. Studies of physiological, genetic, environmental, and pathological factors were included. The main focus was the two ATP-binding cassette (ABC) transporters: P-glycoprotein 170 (Pgp) and Breast Cancer Resistance Protein (BCRP).

Quantification of transport protein mRNAs along the human intestine indicated that eight of the nine investigated drug transporters were expressed in a region-dependent manner. Effects of drug-drug interactions may therefore vary depending on the site of absorption. The genetic aspect was illustrated by identification of sequence variation in the gene encoding BCRP, the most highly expressed ABC transporter along the human intestine. Drug-drug interactions are important environmental causes of interindividual variability. An evaluation of the effects of Pgp-mediated drug-drug interactions showed that patients receiving Pgp inhibitors had elevated serum concentrations of the Pgp substrate digoxin and that digoxin concentrations were positively correlated with the number of co-administered Pgp inhibitors. The final topic in this thesis was that of drug-disease interactions. BCRP and Pgp were down-regulated during active inflammation in patients with ulcerative colitis. This may contribute to altered concentrations of drug in the intestinal mucosa during periods of inflammation and possibly to changes in drug absorption.

To summarize, results of this thesis emphasize the complex background to the interindividual variability of drug transport proteins, where physiological, genetic, environmental and pathological factors all can contribute.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 66 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 21
Pharmaceutics, membrane transport proteins, ATP-Binding Cassette Transporters, P-glycoprotein, Breast Cancer Resistance Protein, Interindividual variability, Galenisk farmaci
National Category
Pharmaceutical Sciences
urn:nbn:se:uu:diva-6127 (URN)91-554-6396-7 (ISBN)
Public defence
2005-12-09, Room B42, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2005-11-17 Created: 2005-11-17 Last updated: 2012-03-19Bibliographically approved

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