P-Glycoprotein and Breast Cancer Resistance Protein Affect Disposition of Tandutinib, A Tyrosine Kinase Inhibitor

Johnny      J. Yang; Mark      N. Milton; Shaoxia      Yu; Mingxiang      Liao; Ning      Liu; Jing-Tao      Wu; Liang-Shang      Gan; Suresh      K. Balani; Frank      W. Lee; Shimoga      Prakash; Cindy      Q. Xia

doi:10.2174/187231210792928279

Abstract

Tandutinib is a tyrosine kinase inhibitor under investigation for the treatment of solid and hematological tumors. We evaluated efflux transporter substrate specificity of tandutinib in Caco-2 cells, and the role of efflux transporters in the disposition of tandutinib in rats and efflux transporter knock-out mice. These studies demonstrated that tandutinib is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) in Caco-2 cells. In rats, administration of GF120918, before treatment with tandutinib orally resulted in approximately a seven-fold increase in the mean plasma area under the concentration-versus-time curve (AUC) compared to the vehicle control group. In mice, after intravenous administration of tandutinib, the mean plasma AUC values in the Bcrp1(-/-) mice and Mdr1a/b(-/-) mice was 1.53- and 1.20-fold greater than that of the wild type (WT) mice, respectively. After oral administration, the drug exposure in Mdr1a/b(-/-), Bcrp1(-/-), and Mdr1a/b(-/-)/Bcrp1(-/-) mice was higher than in the WT mice. The brain to plasma exposure ratio (B/P) of tandutinib in Mdr1a/b(-/-) mice increased by 2- to 3-fold over that in the WT mice. There was a 13-fold increase in B/P in Mdr1a/b(-/-)/Bcrp1(-/-) mice. This finding illustrates that P-gp and Bcrp play a role in oral absorption, systemic clearance, and brain penetration of tandutinib in the rodents. P-gp affected oral absorption and brain penetration of tandutinib to a greater extent than Bcrp, but Bcrp contribution to systemic clearance of tandutinib was greater than Pgp. Thus, co-administration of efflux pump inhibitors may be a useful strategy to enhance tandutinib absorption and brain penetration clinically.

Keywords: Tandutinib, P-gp, BCRP, drug disposition, pharmacokinetics, transporter knock-out mouse, rat, Breast Cancer, Tyrosine Kinase, hematological tu-mors, breast cancer resistance protein (BCRP), tandutinib absorption, platelet-derived gro-wth factor receptor (PDGFR), c-KIT receptor tyrosine kina, (CSF-1R), leukemia, acute myelogenous leukemia, blood-brain barrier, multi-drug resistance 1, anti-tumor agents, gefitinib, imatinib, central nervous system (CNS), Bcrp KO mice, Cell Culture, Dulbecco's Modified Eagle's Medium (DMEM), Transporter Inhibitors, Efflux Transporters, micro-plate scintillation, estrone-3-sulfate, liquid chromatography (HPLC), re-versed-phase column, P-gp inhibitor, BCRP-mediated efflux, quinazoline structure, Topotecan, nitrofurantoin, hydrophilic glycoprotein, lapatinib, dasatinib, gefit-inib, antie-pileptic drug (AED), gastrointestinal tract, drug-drug interactions