Effect of the drug transporters ABCG2, Abcg2, ABCB1 and ABCC2 on the disposition, brain accumulation and myelotoxicity o
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PRECLINICAL STUDIES
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 Marchetti & Dick Pluim & Monique van Eijndhoven & Olaf van Tellingen & Roberto Mazzanti & Jos H. Beijnen & Jan H. M. Schellens
Received: 10 October 2012 / Accepted: 1 January 2013 / Published online: 13 January 2013 # Springer Science+Business Media New York 2013
Summary We explored whether barasertib (AZD1152), a selective Aurora B kinase inhibitor, is a substrate for Pglycoprotein (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,
S. Marchetti : D. Pluim : M. van Eijndhoven : O. van Tellingen : J. H. M. Schellens Department of Experimental Therapy and Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands J. H. Beijnen : J. H. M. Schellens Science Faculty, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands R. Mazzanti Medical Oncology Unit 2, Azienda Ospedaliero-Universitaria Careggi, University of Florence, Florence, Italy
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
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