Investigational New Drugs

, Volume 31, Issue 5, pp 1125–1135 | Cite as

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

  • Serena MarchettiEmail author
  • Dick Pluim
  • Monique van Eijndhoven
  • Olaf van Tellingen
  • Roberto Mazzanti
  • Jos H. Beijnen
  • Jan H. M. Schellens


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.


Barasertib AZD1152 Drug efflux transporters BCRP P-glycoprotein MRP2 Aurora kinase 


Conflict of interest

The authors disclose no potential conflict of interest.


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Serena Marchetti
    • 1
    • 4
    Email author
  • Dick Pluim
    • 1
  • Monique van Eijndhoven
    • 1
  • Olaf van Tellingen
    • 1
  • Roberto Mazzanti
    • 3
  • Jos H. Beijnen
    • 2
  • Jan H. M. Schellens
    • 1
    • 2
  1. 1.Department of Experimental Therapy and Medical OncologyThe Netherlands Cancer InstituteAmsterdamthe Netherlands
  2. 2.Science Faculty, Department of Pharmaceutical SciencesUtrecht UniversityUtrechtthe Netherlands
  3. 3.Medical Oncology Unit 2Azienda Ospedaliero-Universitaria Careggi, University of FlorenceFlorenceItaly
  4. 4.Department of Clinical PharmacologyThe Netherlands Cancer InstituteAmsterdamThe Netherlands

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