title: P-glycoprotein and breast cancer resistance protein affect disposition of tandutinib, a tyrosine kinase inhibitor.
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 P-gp. Thus, co-administration of efflux pump inhibitors may be a useful strategy to enhance tandutinib absorption and brain penetration clinically.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Millennium Pharmaceuticals Inc., Takeda Oncology Company, 40 Landsdowne Street, Cambridge, MA 02139, USA. johnny.yang@mpi.com
authors.forename: Johnny J
authors.initials: JJ
authors.lastname: Yang
authors.forename: Mark N
authors.initials: MN
authors.lastname: Milton
authors.forename: Shaoxia
authors.initials: S
authors.lastname: Yu
authors.forename: Mingxiang
authors.initials: M
authors.lastname: Liao
authors.forename: Ning
authors.initials: N
authors.lastname: Liu
authors.forename: Jing-Tao
authors.initials: JT
authors.lastname: Wu
authors.forename: Liangshang
authors.initials: L
authors.lastname: Gan
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Balani
authors.forename: Frank W
authors.initials: FW
authors.lastname: Lee
authors.forename: Shimoga
authors.initials: S
authors.lastname: Prakash
authors.forename: Cindy Q
authors.initials: CQ
authors.lastname: Xia
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000166:Acridines / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D001692:Biological Transport; D001921:Brain / Q000378:metabolism; D018938:Caco-2 Cells; D006801:Humans; D007275:Injections, Intravenous; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011799:Quinazolines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D009363:Neoplasm Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D044005:Tetrahydroisoquinolines; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; C501412:Abcg2 protein, mouse; C489249:Abcg2 protein, rat; C095122:multidrug resistance protein 3; C464670:tandutinib; C083501:Elacridar