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

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 delivery of P-gp substrates into brain by several-fold. 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)–11C-verapamil. Methods: 5 healthy volunteers underwent paired (R)–11C-verapamil PET scans and arterial blood sampling, before and at 2 h 50 min after i.v. administration of tariquidar (2 mg/kg body weight). Inhibition of P-gp on CD56+ peripheral lymphocytes of each volunteer was determined by means of the rhodamine-123 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, +24±15%) and influx rate constant (K1, +49±36%) of (R)–11C-verapamil across the BBB (DV=0.65±0.13 and 0.80±0.07, p=0.043, K1=0.034±0.009 and 0.049±0.009, p=0.043, before and after tariquidar, respectively). A strong correlation was observed between change in brain DV after administration of tariquidar and tariquidar exposure in plasma (r=0.90, p=0.037). The mean plasma concentration of tariquidar achieved during the second PET scan (490±166 ng/mL) corresponded to 100% inhibition of P-gp function in peripheral lymphocytes. Conclusion: Tariquidar significantly increased brain penetration of (R)–11C-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.