title: In vitro characterization of axitinib interactions with human efflux and hepatic uptake transporters: implications for disposition and drug interactions.
abstract: Axitinib is an inhibitor of tyrosine kinase vascular endothelin growth factor receptors 1, 2, and 3. The ATP-binding cassette (ABC) and solute carrier (SLC) transport properties of axitinib were determined in selected cellular systems. Axitinib exhibited high passive permeability in all cell lines evaluated (Papp ≥ 6 × 10(-6) cm/s). Active efflux was observed in Caco-2 cells, and further evaluation in multidrug resistance gene 1 (MDR1) or breast cancer resistance protein (BCRP) transfected Madin-Darby canine kidney cells type 2 (MDCK) cells indicated that axitinib is at most only a weak substrate for P-glycoprotein (P-gp) but not BCRP. Axitinib showed incomplete inhibition of P-gp-mediated transport of digoxin in Caco-2 cells and BCRP transport of topotecan in BCRP-transfected MDCK cells with IC50 values of 3 μM and 4.4 μM, respectively. Axitinib (10 mg) did not pose a risk for systemic drug interactions with P-gp or BCRP per regulatory guidance. A potential risk for drug interactions through inhibition of P-gp and BCRP in the gastrointestinal tract was identified because an axitinib dose of 10 mg divided by 250 mL was greater than 10-fold the IC50 for each transporter. However, a GastroPlus simulation that considered the low solubility of axitinib resulted in lower intestinal concentrations and suggested a low potential for gastrointestinal interactions with P-gp and BCRP substrates. Organic anion transporting polypeptide 1B1 (OATP1B1) and OATP1B3 transfected human embryonic kidney 293 (HEK293) cells transported axitinib to a minor extent but uptake into suspended hepatocytes was not inhibited by rifamycin SV suggesting that high passive permeability predominates. Mouse whole-body autoradiography revealed that [(14)C]axitinib-equivalents showed rapid absorption and distribution to all tissues except the brain. This suggests that efflux transport of axitinib may occur at the mouse blood-brain barrier.
authors.affiliation: Genentech, Inc., South San Francisco, CA, USA.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Reyner
authors.forename: Samantha
authors.initials: S
authors.lastname: Sevidal
authors.forename: Mark A
authors.initials: MA
authors.lastname: West
authors.forename: Andrea
authors.initials: A
authors.lastname: Clouser-Roche
authors.forename: Sascha
authors.initials: S
authors.lastname: Freiwald
authors.forename: Katherine
authors.initials: K
authors.lastname: Fenner
authors.forename: Mohammed
authors.initials: M
authors.lastname: Ullah
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Lee
authors.forename: Bill J
authors.initials: BJ
authors.lastname: Smith
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000502:physiology*; D000818:Animals; D001345:Autoradiography; D000077784:Axitinib; D018938:Caco-2 Cells; D004347:Drug Interactions; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000378:metabolism*; D007191:Indazoles / Q000737:chemistry / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D010539:Permeability; D047428:Protein Kinase Inhibitors / Q000378:metabolism*; D018570:Risk Assessment; D012995:Solubility
chemical_list: C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D007093:Imidazoles; D007191:Indazoles; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D000077784:Axitinib