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Substrate and method dependent inhibition of three ABC-transporters (MDR1, BCRP, and MRP2)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy. QPS LLC, Durham, NC USA..
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.ORCID iD: 0000-0002-8917-2612
AstraZeneca R&D Gothenburg, Pharmaceut Technol & Dev, SE-43183 Molndal, Sweden..
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2017 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 103, 70-76 p.Article in journal (Refereed) Published
Abstract [en]

Drug transport and drug-drug interactions (DDI) with human ABC transporters are generally investigated in mammalian cell lines or inverted membrane vesicles from insect cells (Sf9) overexpressing the transporter of interest. In this study, we instead used membrane vesicles from human embryonic kidney cells (HEK293) overexpressing wild type MDR1/Pgp (ABCB1), BCRP (ABCG2), and MRP2 (ABCC2) with the aim to study the concentration dependent inhibition of shared and prototypic probe substrates. We first investigated 15 substrates and identified estrone-17-beta-glucorinide (E17G) as shared substrate. Nine specific and general inhibitors were then studied using El7G and prototypic probe substrates. The results were compared with those previously obtained in Sf9 vesicles and cell lines of canine (MDCKII) and human (Saos-2) origin. For the majority of inhibitors, K-i; values differed <10-fold between EI7G and probe substrates. Significant differences in K-i; values were observed for about one third of the inhibitors. The transport inhibition potencies in HEK293 vesicles were in good agreement with those obtained in Sf9 vesicles. Large differences were found in the inhibition potencies observed in the vesicular systems compared to the cellular systems. Nevertheless, the rank order correlations between the different experimental systems were generally good. Our study provides further information on substrate dependent inhibition of ABC-transporters, and suggests that simple ranking of compounds can be used as a tier one approach to bridge results obtained in different experimental systems.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV , 2017. Vol. 103, 70-76 p.
Keyword [en]
Transport protein, ATP binding cassette transporter, Transport inhibition, DDI drug-drug-interaction, Membrane vesicles, HEK293
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-326226DOI: 10.1016/j.ejps.2017.03.002ISI: 000402349700009PubMedID: 28263911OAI: oai:DiVA.org:uu-326226DiVA: diva2:1119481
Funder
Swedish Research Council, 521-2009-4085, 521-2009-2651
Available from: 2017-07-04 Created: 2017-07-04 Last updated: 2017-07-04Bibliographically approved

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Khan, Elin K.Bergström, ChristelArtursson, Per
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