Abstract 966: Effect of ABC drug transporters (BCRP, MDR1, MRP2) on the disposition, brain accumulation and myelotoxicity of the aurora kinase B inhibitor barasertib and its more active form barasertib-hydroxy-QPA .
Authors: Marchetti Serena , Pluim Dick , van Eijndhoven Monique , van Tellingen Olaf , Mazzanti Roberto , Beijnen Jos , Schellens Jan HM 
Published: August 2014

In our studies we explore whether barasertib (AZD1152), a novel Aurora B kinase inhibitor, and its more active form barasertib-hQPA, is a substrate drug for the main ABC transporter pumps in vitro and in vivo. We tested this in vitro by using barasertib and barasertib-hQPA in cell survival, drug transport, and competition experiments using MDCKII (wild type, and overexpressing -MDR1, -BCRP, and -MRP2) and LLCPK (wild type and overexpressing -MDR1) cells and monolayers, and Sf9-BCRP membrane vesicles. In vivo, we tested whether P-gp and BCRP affect the oral pharmacokinetics, tissue distribution, and myelotoxicity of barasertib in wild type mice and in the combined P-glycoprotein (Pgp) and Bcrp1 negative mice (Bcrp1−/−/Mdr1a/1b−/−), which model was developed at our institute.

In cell survival experiments expression of BCRP and MDR1 resulted in significant resistance to barasertib. Compared with parental ones, MDCKII-Bcrp1 cells were 57-fold and 97-fold resistant to barasertib and barasertib-hQPA, respectively, whereas MDCKII-MDR1 cells were 7.8- and 12.5-fold resistant to barasertib and barasertib-hQPA, respectively.

In transwell experiments, barasertib-hQPA was transported by BCRP and MDR1 efficiently and transport could be inhibited by the BCRP blockers elacridar (5 μM) or pantoprazole (500 μM) and by the P-gp inhibitor zosuquidar, respectively. In Sf9-BCRP membrane vesicles, both barasertib and barasertib-hQPA significantly inhibited the BCRP-mediated transport of methotrexate in a concentration dependent manner. In contrast, no active transport of barasertib by MRP2 was observed, and overexpression of MRP2 did not affect cytotoxicity of barasertib.

In vivo, area under the curve (AUC) of barasertib-hQPA after oral dosing (10 mg/kg) in Bcrp1−/−/Mdr1a/1b−/− was 27-fold higher than in wild type mice (p&lt;0.001). The maximal plasma concentration in Bcrp1−/−/Mdr1a/1b−/− was 22-fold higher than in wild type mice (p&lt;0.001). Intraperitoneal pharmacokinetics were not significantly different in Bcrp1−/−/Mdr1a/1b−/− and wild type mice. Moreover, brain penetration, kidney and liver distribution as well as myelotoxicity of barasertib-hQPA were statistically significantly increased in Bcrp1/Mdr1a/1b−/− compared with wild type mice (p&lt;0.001).

Our results suggest that 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 should be considered.

Citation Format: Serena Marchetti, Dick Pluim, Monique van Eijndhoven, Olaf van Tellingen, Roberto Mazzanti, Jos Beijnen, Jan HM Schellens. Effect of ABC drug transporters (BCRP, MDR1, MRP2) on the disposition, brain accumulation and myelotoxicity of the aurora kinase B inhibitor barasertib and its more active form barasertib-hydroxy-QPA . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 966. doi:10.1158/1538-7445.AM2013-966