uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
A Global Drug Inhibition Pattern for the Human ATP-Binding Cassette Transporter Breast Cancer Resistance Protein (ABCG2)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
Show others and affiliations
2007 (English)In: Journal of Pharmacology and Experimental Therapeutics, ISSN 0022-3565, E-ISSN 1521-0103, Vol. 323, no 1, 19-30 p.Article in journal (Refereed) Published
Abstract [en]

In this article, we explore the entire structural space of registered drugs to obtain a global model for the inhibition of the drug efflux transporter breast cancer resistance protein (BCRP; ABCG2). For this purpose, the inhibitory effect of 123 structurally diverse drugs and drug-like compounds on mitoxantrone efflux was studied in Saos-2 cells transfected with human wild-type (Arg482) BCRP. The search for BCRP inhibitors throughout the drug-like chemical space resulted in the identification of 29 previously unknown inhibitors. The frequency of BCRP inhibition was 3 times higher for compounds reported to interact with other ATP-binding cassette (ABC) transporters than for compounds without reported ABC transporter affinity. An easily interpreted computational model capable of discriminating inhibitors from noninhibitors using only two molecular descriptors, octanol-water partition coefficient at pH 7.4 and molecular polarizability, was constructed. The discriminating power of this two-descriptor model was 93% for the training set and 79% for the test set, respectively. The results were supported by a global pharmacophore model and are in agreement with a two-step mechanism for the inhibition of BCRP, where both the drug's capacity to insert into the cell membrane and to interact with the inhibitory binding site of the transporter are important.

Place, publisher, year, edition, pages
2007. Vol. 323, no 1, 19-30 p.
Keyword [en]
ATP-Binding Cassette Transporters/*antagonists & inhibitors/genetics/metabolism, Amino Acid Substitution, Antineoplastic Agents/*chemistry/*pharmacology, Arginine/genetics/physiology, Binding; Competitive, Biological Transport, Cell Line, Computational Biology, Drug Resistance; Neoplasm, Humans, Mitoxantrone/pharmacokinetics, Neoplasm Proteins/*antagonists & inhibitors/genetics, Protein Binding, Structure-Activity Relationship
National Category
Pharmaceutical Sciences
URN: urn:nbn:se:uu:diva-96582DOI: 10.1124/jpet.107.124768ISI: 000249588900003PubMedID: 17616561OAI: oai:DiVA.org:uu-96582DiVA: diva2:171207
Available from: 2007-12-20 Created: 2007-12-20 Last updated: 2016-05-03Bibliographically 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

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed

Search in DiVA

By author/editor
Matsson, PärAhlin, GustavBergström, Christel A. S.Norinder, UlfArtursson, Per
By organisation
Department of Pharmacy
In the same journal
Journal of Pharmacology and Experimental Therapeutics
Pharmaceutical Sciences

Search outside of DiVA

GoogleGoogle Scholar

Altmetric score

Total: 216 hits
ReferencesLink to record
Permanent link

Direct link