Dose-response assessment of tariquidar and elacridar and regional quantification of P-glycoprotein inhibition at the rat blood-brain barrier using (R)-[11C]verapamil PET

Abstract

Purpose-Overactivity of the multidrug efflux transporter P-glycoprotein (P-gp) at the bloodbrain barrier (BBB) is believed to play an important role in resistance to central nervous system drug treatment. (R)-[ 11 C]verapamil (VPM) PET can be used to measure the function of P-gp at the BBB, but low brain uptake of VPM hampers the mapping of regional differences in cerebral P-gp function and expression. The aim of this study was to evaluate the dose-response relationship of two potent P-gp inhibitors and to investigate if increased brain uptake of VPM mediated by P-gp inhibition can be used to assess regional differences in P-gp activity.Methods-Two groups of Sprague-Dawley rats (n=12) underwent single VPM PET scans at 120 min after administration of different doses of the P-gp inhibitors tariquidar and elacridar. In an additional 6 rats, paired VPM PET scans were performed before and after administration of 3 mg/ kg tariquidar.Results-Inhibitor administration resulted in an up to 11-fold increase in VPM brain distribution volumes (DV) with ED 50 values of 3.0±0.2 and 1.2±0.1 mg/kg for tariquidar and elacridar, respectively. In paired PET scans, 3 mg/kg tariquidar resulted in regionally different enhancement of brain activity distribution, with lowest DV in cerebellum and highest DV in thalamus.Conclusion-Our data show that tariquidar and elacridar are able to increase VPM brain distribution in rat brain up to 11-fold over baseline at maximum effective doses, with elacridar being about 3 times more potent than tariquidar. Regional differences in tariquidar-induced modulation of VPM brain uptake point to regional differences in cerebral P-gp function and expression in rat brain.

Altered GABAA Receptor Density and Unaltered Blood–Brain Barrier Transport in a Kainate Model of Epilepsy: An In Vivo Study Using 11C-Flumazenil and PET

“…Both clinical and preclinical studies have reported small, but significant, regional differences in increasing concentrations of the P-gp substrate radiotracer (R)-11 Cverapamil after P-gp inhibition (16,34,35). In contrast, effects of tariquidar on Q out and V br were similar in all brain regions studied in the present study (Table 4).…”

“…Tariquidar, 3 (n 5 6) or 15 (n 5 23) mgÁkg 21 , was administered as an infusion over 10 min, starting 20 min before the second scan. The tariquidar doses were based on studies showing that 15 mg/kg results in complete inhibition of P-gp and 3 mg/kg is close to the median effective dose (16). The lower dose of 3 mg/kg can also be used in humans and could potentially allow for the translation of results between preclinical and clinical studies.…”

Coadministration of P-Glycoprotein Modulators on Loperamide Pharmacokinetics and Brain Distribution

“…The choice of loperamide as a P-gp substrate and its dose was based on its opiate-like behavior, which provides an efficient means with which to ascertain the blockage of the P-gp (Elkiweri et al, 2009). Because the reported ED 50 values for tariquidar and elacridar in rats (Kuntner et al, 2010) were lethal in coadministration with loperamide in our pilot study, the doses of the P-gp modulators were reduced to 0.5 or 1.0 mg/kg.…”

Use of the Cassette-Dosing Approach to Assess Brain Penetration in Drug Discovery

“…Elacridar is a third-generation P-gp inhibitor with K i of 1.6 nM for P-gp inhibition and is also a potent Bcrp inhibitor with in vitro EC 90 of 51 to 61 nM (Allen et al, 2002;Sugimoto et al, 2011). Its in vivo mouse and rat plasma IC 50 for inhibition of P-gp at the BBB ranged from 114 to 282 ng/ml, and its IC 50 for inhibition of Bcrp was 790 ng/ml determined in a brain perfusion study (Cutler et al, 2006;Bihorel et al, 2007;Oostendorp et al, 2009;Kuntner et al, 2010;Sugimoto et al, 2011). Thus, with 2-fold as a cutoff value for the effects of elacridar on K p , no change for the K p values of P-gp and/or Bcrp substrates occurs when elacridar plasma concentrations are below 114 ng/ml.…”