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Cyclosporin A, tacrolimus and sirolimus are potent inhibitors of the human breast cancer resistance protein (ABCG2) and reverse resistance to mitoxantrone and topotecan

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Abstract

Purpose: Several studies have demonstrated significant interactions between immunosuppressants (e.g., cyclosporin A) and chemotherapeutic drugs that are BCRP substrates (e.g., irinotecan), resulting in increased bioavailability and reduced clearance of these agents. One possible mechanism underlying this observation is that the immunosuppressants modulate the pharmacokinetics of these drugs by inhibiting BCRP. Therefore, the aim of this study was to determine whether the immunosuppressants cyclosporin A, tacrolimus and sirolimus are inhibitors and/or substrates of BCRP. Methods: First, the effect of the immunosuppressants on BCRP efflux activity in BCRP-expressing HEK cells was measured by flow cytometry. Results: Cyclosporin A, tacrolimus and sirolimus significantly inhibited BCRP-mediated efflux of pheophorbide A, mitoxantrone and BODIPY-prazosin. The EC50 values of cyclosporin A, tacrolimus and sirolimus for inhibition of BCRP-mediated pheophorbide A efflux were 4.3±1.9 μM, 3.6±1.8 μM and 1.9±0.4 μM, respectively. Cyclosporin A, tacrolimus and sirolimus also effectively reversed resistance of HEK cells to topotecan and mitoxantrone conferred by BCRP. When direct efflux of cyclosporin A, tacrolimus and sirolimus was measured, these compounds were found not to be transported by BCRP. Consistent with this finding, BCRP did not confer resistance to the immunosuppressants in HEK cells. Conclusion: These results indicate that cyclosporin A, tacrolimus and sirolimus are effective inhibitors but not substrates of BCRP. These findings could explain the altered pharmacokinetics of BCRP substrate drugs when co-administered with the immunosuppressants and suggest that pharmacokinetic modulation by the immunosuppressants may improve the therapeutic outcome of these drugs.

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Acknowledgements

The authors thank Drs. Robert W. Robey and Susan E. Bates (National Cancer Institute, Bethesda, MD) for providing the HEK cell lines and FTC. We also acknowledge GlaxoSmithKline for providing topotecan.

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Authors and Affiliations

  1. Department of Pharmaceutics, School of Pharmacy, University of Washington, 357610, Seattle, WA, 98195-7610, USA

    Anshul Gupta, Yang Dai, R. Robert Vethanayagam, Kenneth E. Thummel, Jashvant D. Unadkat & Qingcheng Mao

  2. Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA, USA

    Mary F. Hebert

  3. University of Maryland Greenebaum Cancer Center and School of Medicine, and the Baltimore VA Medical Center, Baltimore, MA, USA

    Douglas D. Ross

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  1. Anshul Gupta
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  2. Yang Dai
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Correspondence to Qingcheng Mao.

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Grant support: We gratefully acknowledge financial support from NIH grant HD044404 (to QM and JDU) and VA Merit Review grant (to DDR)

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Gupta, A., Dai, Y., Vethanayagam, R.R. et al. Cyclosporin A, tacrolimus and sirolimus are potent inhibitors of the human breast cancer resistance protein (ABCG2) and reverse resistance to mitoxantrone and topotecan. Cancer Chemother Pharmacol 58, 374–383 (2006). https://doi.org/10.1007/s00280-005-0173-6

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