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ATP-Binding Cassette Efflux Transporters and Passive Membrane Permeability in Drug Absorption and Disposition
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmacy.
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. , p. 68
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 67
Keywords [en]
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
Keywords [sv]
Galenisk farmaci
Identifiers
URN: urn:nbn:se:uu:diva-8371ISBN: 978-91-554-7058-6 (print)OAI: oai:DiVA.org:uu-8371DiVA, id: diva2:171210
Public defence
2008-01-18, B21, Uppsala Biomedicinska Centrum BMC, Husargatan 3, Uppsala, 09:15
Opponent
Supervisors
Available from: 2007-12-20 Created: 2007-12-20Bibliographically approved
List of papers
1. Exploring the Role of Different Drug Transport Routes in Permeability Screening
Open this publication in new window or tab >>Exploring the Role of Different Drug Transport Routes in Permeability Screening
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2005 In: Journal of Medicinal Chemistry, ISSN 0022-2623, Vol. 48, no 2, p. 604-613Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-96581 (URN)
Available from: 2007-12-20 Created: 2007-12-20Bibliographically approved
2. A Global Drug Inhibition Pattern for the Human ATP-Binding Cassette Transporter Breast Cancer Resistance Protein (ABCG2)
Open this publication in new window or tab >>A Global Drug Inhibition Pattern for the Human ATP-Binding Cassette Transporter Breast Cancer Resistance Protein (ABCG2)
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2007 (English)In: Journal of Pharmacology and Experimental Therapeutics, ISSN 0022-3565, E-ISSN 1521-0103, Vol. 323, no 1, p. 19-30Article 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.

Keywords
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
Identifiers
urn:nbn:se:uu:diva-96582 (URN)10.1124/jpet.107.124768 (DOI)000249588900003 ()17616561 (PubMedID)
Available from: 2007-12-20 Created: 2007-12-20 Last updated: 2018-07-30Bibliographically approved
3. Prediction and identification of drug interactions with the human ATP-binding cassette transporter multidrug-resistance associated protein 2 (MRP2; ABCC2)
Open this publication in new window or tab >>Prediction and identification of drug interactions with the human ATP-binding cassette transporter multidrug-resistance associated protein 2 (MRP2; ABCC2)
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2008 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, no 11, p. 3275-3287Article in journal (Refereed) Published
Abstract [en]

The chemical space of registered oral drugs was explored for inhibitors of the human multidrug-resistance associated protein 2 (MRP2, ABCC2), using a data set of 191 structurally diverse drugs and drug-like compounds. The data set included a new reference set of 75 compounds, for studies of hepatic drug interactions with transport proteins, CYP enzymes, and compounds associated with liver toxicity. The inhibition of MRP2-mediated transport of estradiol-17 beta-D-glucuronide was studied in inverted membrane vesicles from Sf9 cells overexpressing human MRP2. A total of 27 previously unknown MRP2 inhibitors were identified, and the results indicate an overlapping but narrower inhibitor space for MRP2 compared with the two other major ABC efflux transporters P-gp (ABCB1) and BCRP (ABCG2). In addition, 13 compounds were shown to stimulate the transport of cstradiol-17 beta-D-glucuronide. The experimental results were used to develop a computational model able to discriminate inhibitors from noninhibitors according to their molecular structure, resulting in a predictive power of 86% for the training set and 72% for the test set. The inhibitors were in general larger and more lipophilic and presented a higher aromaticity than the noninhibitors. The developed computational model is applicable in an early stage of the drug discovery process and is proposed as a tool for prediction of MRP2-mediated hepatic drug interactions and toxicity.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-96583 (URN)10.1021/jm7015683 (DOI)000256504800025 ()18457386 (PubMedID)
Available from: 2007-12-20 Created: 2007-12-20 Last updated: 2018-01-13Bibliographically approved
4. Comparison and Prediction of Inhibitors of the Three Major Human ATP-Binding Cassette Transporters P-gp, BCRP and MRP2
Open this publication in new window or tab >>Comparison and Prediction of Inhibitors of the Three Major Human ATP-Binding Cassette Transporters P-gp, BCRP and MRP2
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Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-96584 (URN)
Available from: 2007-12-20 Created: 2007-12-20 Last updated: 2010-01-13Bibliographically approved

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