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Effect of the drug transporters ABCG2, Abcg2, ABCB1 and ABCC2 on the disposition, brain accumulation and myelotoxicity of the aurora kinase B inhibitor barasertib and its more active form barasertib-hydroxy-QPA

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An Erratum to this article was published on 11 April 2013

Summary

We explored whether barasertib (AZD1152), a selective Aurora B kinase inhibitor, is a substrate for P-glycoprotein (Pgp, MDR1), breast cancer resistance protein (BCRP), and multidrug resistance protein 2 (MRP2) in vitro. Cell survival, drug transport, and competition experiments with barasertib pro-drug and the more active form of the drug (barasertib-hQPA) were performed using MDCKII (wild type, MDR1, BCRP, and MRP2) and LLCPK (wild type and MDR1) cells and monolayers, and Sf9-BCRP membrane vesicles. Moreover we tested whether P-gp and BCRP affect the oral pharmacokinetics, tissue distribution, and myelotoxicity of barasertib in vivo using Bcrp1-/-/Mdr1a/1b -/- (triple knockout) and wild type mice. In cell survival experiments expression of BCRP and MDR1 resulted in significant resistance to barasertib. In transwell experiments, barasertib-hQPA was transported by BCRP and MDR1 efficiently. In Sf9-BCRP membrane vesicles, both barasertib and barasertib-hQPA significantly inhibited the BCRP-mediated transport of methotrexate. In contrast, no active transport of barasertib by MRP2 was observed, and overexpression of MRP2 did not affect cytotoxicity of barasertib. In vivo, systemic exposure as well as bioavailability, brain penetration, kidney and liver distribution and myelotoxicity of barasertib-hQPA were statistically significantly increased in Bcrp1-/-/Mdr1a/1b-/- compared with wild type mice (p<0.001). Barasertib is transported efficiently by P-gp and BCRP/Bcrp1 in vitro. In vivo, genetic deletion of P-gp and BCRP in mice significantly affected pharmacokinetics, tissue distribution and myelotoxicity of barasertib-hQPA. Possible clinical consequences for the observed affinity of barasertib for P-gp and BCRP need to be explored.

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Authors and Affiliations

  1. Department of Experimental Therapy and Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands

    Serena Marchetti, Dick Pluim, Monique van Eijndhoven, Olaf van Tellingen & Jan H. M. Schellens

  2. Science Faculty, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands

    Jos H. Beijnen & Jan H. M. Schellens

  3. Medical Oncology Unit 2, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Florence, Italy

    Roberto Mazzanti

  4. Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    Serena Marchetti

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  1. Serena Marchetti
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Correspondence to Serena Marchetti.

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Marchetti, S., Pluim, D., van Eijndhoven, M. et al. Effect of the drug transporters ABCG2, Abcg2, ABCB1 and ABCC2 on the disposition, brain accumulation and myelotoxicity of the aurora kinase B inhibitor barasertib and its more active form barasertib-hydroxy-QPA. Invest New Drugs 31, 1125–1135 (2013). https://doi.org/10.1007/s10637-013-9923-1

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