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 transporterknockout mice as well as in in vitro transport assays in MDToverexpressing cells.

Pilocarpine-Induced Convulsive Activity Is Limited by Multidrug Transporters at the Rodent Blood-Brain Barrier

“…Similar observations have been made for other substrates of PGP and BCRP (de Vries et al, 2007;Chen et al, 2009;Polli et al, 2009). Furthermore, pretreatment of WT mice with 15 mg×kg 21 of the dual PGP and BCRP inhibitor tariquidar (Bankstahl et al, 2013) resulted in increased pilocarpine brain uptake to a degree comparable with PGP/ BCRP-deficient mice, underscoring that pilocarpine is indeed transported by both multidrug transporters. Interestingly, in Bcrp1 (2/2) mice we did not observe increased pilocarpine brain uptake, although in vitro results clearly show BCRP-mediated transport.…”

“…Again, this finding may be explained by a compensatory overexpression of other transporters in Bcrp1 (2/2) mice. In addition, many compounds interacting with multidrug transporters are described to behave dose dependently as both substrate and inhibitor (Bankstahl et al, 2013). Further studies are needed to determine whether this concept may be applicable for pilocarpine.…”

“…Fifty milligrams per kilogram pilocarpine were administered intraperitoneally to all four mouse genotypes (n 5 6 per group). A separate group of WT mice (n 5 6) received an injection of 15 mg×kg 21 tariquidar intravenously 1 hour before pilocarpine for complete inhibition of PGP and partial inhibition of BCRP (Bankstahl et al, 2013). A further group (n 5 6) were pretreated with 10 mEq×kg 21 (423.3 mg×kg…”

Role of (Drug) Transporters in Imaging in Health and Disease

“…Similarly, as previously demonstrated by us and others (Sasongko et al, 2005;Hsiao et al, 2008;Eyal et al, 2009Eyal et al, , 2010Muzi et al, 2009;Bauer et al, 2012;Mullauer et al, 2012;Bankstahl et al, 2013;Ke et al, 2013;Deo et al, 2014), when a drug is effluxed out of the brain, its concentration in the brain can be much lower than that in the plasma. This disconnect between tissue and plasma drug concentration will be modulated in the presence of a drug-drug interaction (DDI).…”

How to overcome ATP-binding cassette drug efflux transporter-mediated drug resistance?

“…Some tariquidar analogs with sulfonamide groups are P-gp specific, nevertheless tariquidar was toxic to healthy cells [107] . Since its discovery, tariquidar was described as non-competitive and non-transported inhibitor of P-gp [110] , while Bankstahl et al [111] have shown that tariquidar is concentration-dependently transported by P-gp. Recent transepithelial drug transport assays using radioactive tariquidar in human and mouse cell lines indicate that tariquidar functions as a high-affinity P-gp substrate rather than a non-competitive inhibitor [112] .…”