title: Tariquidar and elacridar are dose-dependently transported by P-glycoprotein and Bcrp at the blood-brain barrier: a small-animal positron emission tomography and in vitro study.
abstract: Elacridar (ELC) and tariquidar (TQD) are generally thought to be nontransported inhibitors of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP), but recent data indicate that they may also be substrates of these multidrug transporters (MDTs). The present study was designed to investigate potential transport of ELC and TQD by MDTs at the blood-brain barrier at tracer doses as used in positron emission tomography (PET) studies. We performed PET scans with carbon-11-labeled ELC and TQD before and after MDT inhibition in wild-type and transporter-knockout mice as well as in in vitro transport assays in MDT-overexpressing cells. Brain entrance of [(11)C]ELC and [(11)C]TQD administered in nanomolar tracer doses was found to be limited by Pgp- and Bcrp1-mediated efflux at the mouse blood-brain barrier. At higher, MDT-inhibitory doses, i.e., 15 mg/kg for TQD and 5 mg/kg for ELC, brain activity uptake of [(11)C]ELC at 25 minutes after tracer injection was 5.8 ± 0.3, 2.1 ± 0.2, and 7.5 ± 1.0-fold higher in wild-type, Mdr1a/b((-/-),()) and Bcrp1((-/-)) mice, respectively, but remained unchanged in Mdr1a/b((-/-))Bcrp1((-/-)) mice. Activity uptake of [(11)C]TQD was 2.8 ± 0.2 and 6.8 ± 0.4-fold higher in wild-type and Bcrp1((-/-)) mice, but remained unchanged in Mdr1a/b((-/-)) and Mdr1a/b((-/-))Bcrp1((-/-)) mice. Consistent with the in vivo findings, in vitro uptake assays in Pgp- and Bcrp1-overexpressing cell lines confirmed low intracellular accumulation of ELC and TQD at nanomolar concentrations and increased uptake at micromolar concentrations. As this study shows that microdoses can behave pharmacokinetically differently from MDT-inhibitory doses if a compound interacts with MDTs, conclusions from microdose studies should be drawn carefully.
authors.affiliation: Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, and Center for Systems Neuroscience, Hannover, Germany. bankstahl.jens@mh-hannover.de
authors.forename: Jens P
authors.initials: JP
authors.lastname: Bankstahl
authors.forename: Marion
authors.initials: M
authors.lastname: Bankstahl
authors.forename: Kerstin
authors.initials: K
authors.lastname: Römermann
authors.forename: Thomas
authors.initials: T
authors.lastname: Wanek
authors.forename: Johann
authors.initials: J
authors.lastname: Stanek
authors.forename: Albert D
authors.initials: AD
authors.lastname: Windhorst
authors.forename: Maren
authors.initials: M
authors.lastname: Fedrowitz
authors.forename: Thomas
authors.initials: T
authors.lastname: Erker
authors.forename: Markus
authors.initials: M
authors.lastname: Müller
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Löscher
authors.forename: Oliver
authors.initials: O
authors.lastname: Langer
authors.forename: Claudia
authors.initials: C
authors.lastname: Kuntner
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / 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 / Q000493:pharmacokinetics*; D000818:Animals; D001692:Biological Transport / Q000235:genetics; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D002250:Carbon Radioisotopes; D002461:Cell Line, Transformed; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D005260:Female; D059907:Functional Neuroimaging; D051379:Mice; D018345:Mice, Knockout; D011804:Quinolines / Q000493:pharmacokinetics*; D011877:Radionuclide Imaging; D044005:Tetrahydroisoquinolines / 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; D000166:Acridines; D002250:Carbon Radioisotopes; D004791:Enzyme Inhibitors; D011804:Quinolines; D044005:Tetrahydroisoquinolines; C402343:tariquidar; C083501:Elacridar