A Pilot Study to Assess the Efficacy of Tariquidar to Inhibit P-glycoprotein at the Human Blood–Brain Barrier with (R)-¹¹C-Verapamil and PET

Abstract

Tariquidar, a potent, nontoxic, third-generation P-glycoprotein (P-gp) inhibitor, is a possible reversal agent for central nervous system drug resistance. In animal studies, tariquidar has been shown to increase the delivery of P-gp substrates into the brain by severalfold. The aim of this study was to measure P-gp function at the human blood-brain barrier (BBB) after tariquidar administration using PET and the model P-gp substrate (R)-11 C-verapamil. Methods: Five healthy volunteers underwent paired (R)-11 C-verapamil PET scans and arterial blood sampling before and at 2 h 50 min after intravenous administration of tariquidar (2 mg/kg of body weight). The inhibition of P-gp on CD56-positive peripheral lymphocytes of each volunteer was determined by means of the 123 Rh efflux assay. Tariquidar concentrations in venous plasma were quantified using liquid chromatography/mass spectrometry. Results: Tariquidar administration resulted in significant increases (Wilcoxon test for paired samples) in the distribution volume (DV, 124% 6 15%) and influx rate constant (K 1 , 149% 6 36%) of (R)-11 C-verapamil across the BBB (DV, 0.65 6 0.13 and 0.80 6 0.07, P 5 0.043; K 1 , 0.034 6 0.009 and 0.049 6 0.009, P 5 0.043, before and after tariquidar administration, respectively). A strong correlation was observed between the change in brain DV after administration of tariquidar and tariquidar exposure in plasma (r 5 0.90, P 5 0.037). The mean plasma concentration of tariquidar achieved during the second PET scan (490 6 166 ng/mL) corresponded to 100% inhibition of P-gp function in peripheral lymphocytes. Conclusion: Tariquidar significantly increased brain penetration of (R)-11 C-verapamil-derived activity due to increased influx. As opposed to peripheral P-gp function, central P-gp inhibition appeared to be far from complete after the administered tariquidar dose.

Behavioral Effects and Central Nervous System Levels of the Broadly Available κ-Agonist Hallucinogen Salvinorin A Are Affected by P-Glycoprotein Modulation In Vivo

“…The selected dose ranges for loperamide and tariquidar were consistent with studies that focused on their pharmacodynamic profile in humans or nonhuman primates, including PET studies of P-glycoprotein function (Butelman et al, 2008;Wagner et al, 2009;Bauer et al, 2010;Kreisl et al, 2010). The similarity of these conditions is supportive of the translational value of these simple behavioral and CNS penetration measures (see below) as endpoints to study P-glycoprotein modulation in vivo.…”

Characterization of P-Glycoprotein Humanized Mice Generated by Chromosome Engineering Technology: Its Utility for Prediction of Drug Distribution to the Brain in Humans

“…Since previously reported P-gp humanized mice did not express functional P-gp at the BBB (Sadiq et al, 2015), the hMDR1-MAC mouse is the first P-gp humanized mouse model expressing functional P-gp in brain capillaries. Furthermore, the mice may be valuable for predicting P-gpmediated drug-drug interactions at the BBB, although the effect of a P-gp inhibitor on the brain distribution of drugs is limited in a clinical setting (Sasongko et al, 2005;Hsiao et al, 2006;Muzi et al, 2009;Wagner et al, 2009;Bauer et al, 2015).…”

Photodynamic therapy of cancer — Challenges of multidrug resistance

“…Nevertheless, Wagner et al demonstrate that the third-generation P-gp modulator tariquidar could inhibit P-gp function at the human blood-brain barrier (BBB), which might be a useful approach for PDT of brain tumor. 56 Recently, Sun et al demonstrated that pretreatment of human glioma cells with Ge¯tinib, a BCRP inhibitor, could enhance intracellular accumulation of PpIX through the inhibition of BCRP expression and BCRP-mediated PpIX e®lux, ultimately improving the e®ectiveness of ALA-PDT. 57 In addition to chronic myelogenous leukemia, thē rst indication for imatinib mesylate (Gleevec or Glivec) for the treatment of solid tumor was approved by the US Food and Drug Administration (FDA) in 2001.…”