Interactions of anti-COVID-19 drug candidates with multispecific ABC and OATP drug transporters

  1. Ágnes Telbisz
  2. Csilla Ambrus
  3. Orsolya Mózner
  4. Edit Szabó
  5. György Várady
  6. Éva Bakos
  7. Balázs Sarkadi
  8. Csilla Özvegy-Laczka

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Abstract

In the COVID-19 epidemic, several repurposed drugs have been proposed to alleviate the major health effects of the disease. These drugs are often applied together with analgesics or non-steroid anti-inflammatory compounds, and co-morbid patients may also be treated with anticancer, cholesterol-lowering or antidiabetic agents. Since drug ADME-tox properties may be significantly affected by multispecific transporters, here we examined the interactions of the repurposed drugs with the key human multidrug transporters, present in the major tissue barriers and strongly affecting pharmacokinetics. Our in vitro studies, using a variety of model systems, explored the interactions of the antimalarial agents chloroquine and hydroxychloroquine, the antihelmintic ivermectin, and the proposed antiviral compounds, ritonavir, lopinavir, favipiravir and remdesivir with the ABCB1/Pgp, ABCG2/BCRP and ABCC1/MRP1 exporters, as well as the OATP2B1 and OATP1A2 uptake transporters. The results presented here show numerous pharmacologically relevant transporter interactions and may provide a warning for the potential toxicities of these repurposed drugs, especially in drug combinations at the clinic.

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  1. ScreenIT

    SciScore for 10.1101/2020.11.21.392555: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    For assaying the function of the ABC transporters in cell-based assays we applied the stable cell lines expressing these transporters: ABCG2 PLB-985, ABCB1 PLB-985, ABCC1 HL-60, and their parental lines that lack significant ABC transporter expression[44].
    HL-60
    suggested: CLS Cat# 300209/p671_HL-60, RRID:CVCL_0002)
    For the ABCG2 transport assay, we have also used HeLa cells stably expressing the wild-type or Q141K polymorphic variant of the ABCG2 protein (see below).
    HeLa
    suggested: None
    These cells were sorted for similar levels of eGFP, and ABCG2 expression was examined by a monoclonal (5D3) antibody-based flow cytometry assay (Q141K-ABCG2 cell surface expression was approximately 80% of the wild type ABCG2 expression.
    Q141K-ABCG2
    suggested: None
    For studying vesicular ATP-dependent transporter activity of the ABC transporters, we used ABCB1/Pgp or ABCG2/BCRP containing HEK-293 cell membrane vesicles, as well as ABCC1/MRP1 containing Sf9 membrane vesicles, prepared by Solvo Biotechnology.
    HEK-293
    suggested: CLS Cat# 300192/p777_HEK293, RRID:CVCL_0045)
    Software and Algorithms
    SentencesResources
    IC50 values were calculated by nonlinear regression analysis using the Origin2019 software (version 9.6.5.169, OriginLab Corporation, Northampton, MA, USA).
    OriginLab Corporation
    suggested: (Origin, RRID:SCR_014212)
    IC50 values were calculated by nonlinear regression analysis using GraphPad prism software (version 5.01, GraphPad, La Jolla, CA, US).
    GraphPad prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

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  2. Version published to 10.1101/2020.11.21.392555v1 on bioRxiv