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Prediction and identification of drug interactions with the human ATP-binding cassette transporter multidrug-resistance associated protein 2 (MRP2; ABCC2)
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.
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2008 (English)In: Journal of Medicinal Chemistry, ISSN 0022-2623, E-ISSN 1520-4804, Vol. 51, no 11, 3275-3287 p.Article 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.

Place, publisher, year, edition, pages
2008. Vol. 51, no 11, 3275-3287 p.
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-96583DOI: 10.1021/jm7015683ISI: 000256504800025PubMedID: 18457386OAI: oai:DiVA.org:uu-96583DiVA: diva2:171208
Available from: 2007-12-20 Created: 2007-12-20 Last updated: 2017-12-14Bibliographically 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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 67
Keyword
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
Identifiers
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
Opponent
Supervisors
Available from: 2007-12-20 Created: 2007-12-20Bibliographically approved
2. ATP-Binding-Cassette Transporters in Biliary Efflux and Drug-Induced Liver Injury
Open this publication in new window or tab >>ATP-Binding-Cassette Transporters in Biliary Efflux and Drug-Induced Liver Injury
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Membrane transport proteins are known to influence the absorption, distribution, metabolism, excretion and toxicity (ADMET) of drugs. At the onset of this thesis work, only a few structure-activity models, in general describing P-glycoprotein (Pgp/ABCB1) interactions, were developed using small datasets with little structural diversity. In this thesis, drug-transport protein interactions were explored using large, diverse datasets representing the chemical space of orally administered registered drugs. Focus was set on the ATP-binding cassette (ABC) transport proteins expressed in the canalicular membrane of human hepatocytes.

The inhibition of the ABC transport proteins multidrug-resistance associated protein 2 (MRP2/ABCC2) and bile salt export pump (BSEP/ABCB11) was experimentally investigated using membrane vesicles from cells overexpressing the investigated proteins and sandwich cultured human hepatocytes (SCHH). Several previously unknown inhibitors were identified for both of the proteins and predictive in silico models were developed. Furthermore, a clear association between BSEP inhibition and clinically reported drug induced liver injuries (DILI) was identified. For the first time, an in silico model that described combined inhibition of Pgp, MRP2 and breast cancer resistance protein (BCRP/ABCG2) was developed using a large, structurally diverse dataset. Lipophilic weak bases were more often found to be general ABC inhibitors in comparison to other drugs. In early drug discovery, in silico models can be used as predictive filters in the drug candidate selection process and membrane vesicles as a first experimental screening tool to investigate protein interactions.

In summary, the present work has led to an increased understanding of molecular properties important in ABC inhibition as well as the potential influence of ABC proteins in adverse drug reactions. A number of previously unknown ABC inhibitors were identified and predictive computational models were developed.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 67 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 172
Keyword
ABC transport protein, Pgp, P-glycoprotein, ABCB1, BCRP, breast cancer resistance protein, ABCG2, MRP2, multidrug resistance-associated protein 2, ABCC2, BSEP, bile salt export pump, ABCB11, sandwich cultured human hepatocytes, SCHH, drug-induced liver injury, DILI, multivariate data analysis, OPLS
National Category
Pharmaceutical Sciences
Research subject
Pharmaceutics
Identifiers
urn:nbn:se:uu:diva-205355 (URN)978-91-554-8702-7 (ISBN)
Public defence
2013-09-06, B21, Biomedicinskt centrum (BMC), Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2013-08-16 Created: 2013-08-16 Last updated: 2014-04-16

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Bergström, Christel A. S.

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