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Tariquidar and Elacridar Are Dose-Dependently Transported by P-Glycoprotein and Bcrp at the Blood-Brain Barrier: A Small-Animal PET and In-Vitro Study.

Drug Metab Dispos. 2013 Jan 10;

Authors: Bankstahl JP, Bankstahl M, Romermann K, Wanek T, Stanek J, Windhorst AD, Fedrowitz M, Erker T, Muller M, Loscher W, Langer O, Kuntner C


Elacridar and tariquidar are generally thought to be non-transported 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 elacridar and tariquidar 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-labelled elacridar and tariquidar 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]elacridar and [(11)C]tariquidar 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 tariquidar and 5 mg/kg for elacridar, brain activity uptake of [(11)C]elacridar at 25 min 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]tariquidar 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 elacridar and tariquidar at nanomolar concentrations and increased uptake at micromolar concentrations. As this study shows that microdoses can behave pharmacokinetically different from MDT-inhibitory doses if a compound interacts with MDTs, conclusions from microdose studies should be drawn carefully.

PMID: 23305710 [PubMed - as supplied by publisher]