title: 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.
abstract: 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.
authors: Department of Experimental Therapy and Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands, s.marchetti@nki.nl.
authors: Serena
authors: S
authors: Marchetti
authors: Dick
authors: D
authors: Pluim
authors: Monique
authors: M
authors: van Eijndhoven
authors: Olaf
authors: O
authors: van Tellingen
authors: Roberto
authors: R
authors: Mazzanti
authors: Jos H
authors: JH
authors: Beijnen
authors: Jan H M
authors: JH
authors: Schellens
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors; D001682:Biological Availability; D001921:Brain / Q000378:metabolism*; D004285:Dogs; D006454:Hemoglobins; D006801:Humans; D007668:Kidney / Q000378:metabolism; D007958:Leukocyte Count; D008099:Liver / Q000378:metabolism; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D018345:Mice, Knockout; D000089762:Multidrug Resistance-Associated Protein 2; D010755:Organophosphates / Q000494:pharmacology*; D010976:Platelet Count; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D014018:Tissue Distribution
chemical_list: C520647:2-((3-((4-((5-(2-((3-fluorophenyl)amino)-2-oxoethyl)-1H-pyrazol-3-yl)amino)quinazolin-7-yl)oxy)propyl)(ethyl)amino)ethyl dihydrogen phosphate; C000715087:ABCC2 protein, human; D018528:ATP-Binding Cassette Transporters; D006454:Hemoglobins; D000089762:Multidrug Resistance-Associated Protein 2; D010755:Organophosphates; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C531556:AZD 1152-HQPA; D064107:Aurora Kinase B