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Membrane Assays to Characterize Interaction of Drugs with ABCB1

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Abstract

ATP-binding cassette sub-family B member 1 (ABCB1) [P-glycoprotein (P-gp), multidrug resistance protein 1 (MDR1)] can affect the pharmacokinetics, safety, and efficacy of drugs making it important to identify compounds that interact with ABCB1. The ATPase assay and vesicular transport (VT) assay are membrane based assays that can be used to measure the interaction of compounds with ABCB1 at a lower cost and higher throughput compared to cellular-based assays and therefore can be used earlier in the drug development process. To that end, we tested compounds previously identified as ABCB1 substrates and inhibitors for interaction with ABCB1 using the ATPase and VT assays. All compounds tested interacted with ABCB1 in both the ATPase and VT assays. All compounds previously identified as ABCB1 substrates activated ABCB1-mediated ATPase activity in the ATPase assay. All compounds previously identified as ABCB1 inhibitors inhibited the ABCB1-mediated transport in the VT assay. Interestingly, six of the ten compounds previously identified as ABCB1 inhibitors activated the basal ATPase activity in activation assays suggesting that the compounds are substrates of ABCB1 but can inhibit ABCB1 in inhibition assays. Importantly, for ATPase activators the EC50 of activation correlated with the IC50 values from the VT assay showing that interactions of compounds with ABCB1 can be measured with similar levels of potency in either assay. For ATPase nonactivators the IC50 values from the ATPase inhibition and VT inhibition assay showed correlation. These results demonstrate the utility of membrane assays as tools to detect and rank order drug–transporter interactions.

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Acknowledgments

The help of Timea Rosta, MSc in preparation of the manuscript is acknowledged. The work was supported by the following Hungarian Grants: GOP-1.1.1-11-2011-0064, GOP-1.1.1-11-2011-0017 (PRODRUG), FP7 EUSTROKE, HEALTH-F2-2008-202213, XTTPSRT1, OM-00230/2005, TUDAS-1-2006-0029, OMFB-00505/2007, GOP-1.1.1-09/1-2009-0054.

Conflict of interest

SOLVO Biotechnology and Xenotech LLC specialize in development and commercialization of transporter technology applications.

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  1. Solvo Biotechnology, 2 Gyár St., Budaörs, 2040, Hungary

    Zsolt Fekete, Zsuzsanna Rajnai, Tünde Nagy, Katalin Tauberné Jakab, Anita Kurunczi, Katalin Gémes, Krisztina Herédi-Szabó & Peter Krajcsi

  2. Institute of Pharmaceutical Chemistry, University of Szeged, 6 Eötvös St., Szeged, 6720, Hungary

    Ferenc Fülöp

  3. Department of Medical Chemistry, Faculty of General Medicine, University of Szeged, 8 Dóm tér, Szeged, 6720, Hungary

    Gábor K. Tóth

  4. XenoTech L.L.C., 16825 West 116 Street, Lenexa, KS, 66219, USA

    Maciej Czerwinski & Greg Loewen

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  1. Zsolt Fekete
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Fekete, Z., Rajnai, Z., Nagy, T. et al. Membrane Assays to Characterize Interaction of Drugs with ABCB1. J Membrane Biol 248, 967–977 (2015). https://doi.org/10.1007/s00232-015-9804-y

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