title: Gefitinib modulates the function of multiple ATP-binding cassette transporters in vivo.
abstract: The 4-anilinoquinazoline (4-AQ) derivative gefitinib (Iressa) is an oral epidermal growth factor receptor tyrosine kinase inhibitor. Oral administration of 4-AQ molecules, such as gefitinib, inhibits ATP-binding cassette (ABC) transporter-mediated drug efflux and strongly increases the apparent bioavailability of coadministered drug molecules that are transporter substrates. Based on in vitro studies investigating 4-AQ interactions with several transporters, these effects have primarily been attributed to the inhibition of breast cancer resistance protein (BCRP; ABCG2). Although 4-AQ shows in vitro inhibition of P-glycoprotein [multidrug resistance protein (MDR1); ABCB1], the in vivo effect on this and other transporters is not known. In our studies, pretreatment of Abcg2(-/-) and Mdr1(a/b)(-/-) mice with gefitinib increased oral absorption and decreased systemic clearance of topotecan, a model substrate, indicating that additional transporters were inhibited. These results were extended to human orthologues using engineered cell lines to show that gefitinib inhibited the efflux of BCRP and MDR1 substrates and restored vincristine sensitivity in MDR1-expressing cells. Although gefitinib inhibited BCRP more potently than MDR1 (10-fold), the inhibition of both transporters occurred at clinically relevant concentrations (e.g., 1-5 micromol/L). These studies illustrate the broad implications for the therapeutic combination of gefitinib or other 4-AQ molecules with agents that are BCRP and MDR1 substrates. 4-AQ molecules may offer a means to increase the low and variable oral drug absorption of transporter substrates while decreasing interpatient variability and reversing tumor drug resistance.
authors.affiliation: Departments of Pharmaceutical Sciences, Hematology-Oncology, and Molecular Pharmacology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. mark.leggas@uky.edu
authors.forename: Markos
authors.initials: M
authors.lastname: Leggas
authors.forename: John C
authors.initials: JC
authors.lastname: Panetta
authors.forename: Yanli
authors.initials: Y
authors.lastname: Zhuang
authors.forename: John D
authors.initials: JD
authors.lastname: Schuetz
authors.forename: Brad
authors.initials: B
authors.lastname: Johnston
authors.forename: Feng
authors.initials: F
authors.lastname: Bai
authors.forename: Brian
authors.initials: B
authors.lastname: Sorrentino
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhou
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Houghton
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Stewart
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000042:Absorption; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D004347:Drug Interactions; D005260:Female; D000077156:Gefitinib; D006801:Humans; D018374:LLC-PK1 Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009061:Mouth Mucosa / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D013552:Swine; D019772:Topotecan / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000970:Antineoplastic Agents; D011799:Quinazolines; D019772:Topotecan; D000077156:Gefitinib