RT Journal Article
SR Electronic
T1 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
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 754
OP 762
DO 10.1124/dmd.112.049148
VO 41
IS 4
A1 Bankstahl, Jens P.
A1 Bankstahl, Marion
A1 Römermann, Kerstin
A1 Wanek, Thomas
A1 Stanek, Johann
A1 Windhorst, Albert D.
A1 Fedrowitz, Maren
A1 Erker, Thomas
A1 Müller, Markus
A1 Löscher, Wolfgang
A1 Langer, Oliver
A1 Kuntner, Claudia
YR 2013
UL http://dmd.aspetjournals.org/content/41/4/754.abstract
AB 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 [11C]ELC and [11C]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 [11C]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 [11C]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.