In vivo dose finding of tariquidar using (R)-[11C]verapamil µPET.

Introduction Tariquidar (TQD, Xenova, UK) is a third-generation inhibitor of the multidrug efflux transporter P-glycoprotein (P-gp) with potential applications in neurology and oncology in order to increase drug exposure of tissues targeted for treatment. We used small-animal positron emission tomography (µPET) with the P-gp substrate (R)-[¹¹C]verapamil (VPM) in order to measure in vivo the degree of P-gp inhibition at the rat blood-brain barrier (BBB) after administration of different doses of TQD. Methods Wistar Unilever rats received intravenous doses of 0, 1, 3, 5, 7.5 and 15 mg/kg of TQD followed by a 1-hour VPM µPET scan recorded at 2 hours after TQD administration. Brain-to-plasma radioactivity ratios were fitted to a sigmoidal dose-response curve. Results TQD inhibited P-gp-mediated efflux of VPM across the BBB with an apparent half-maximum effective dose (ED₅₀) of 6.6 mg/kg (95% confidence interval: 4.9-8.2 mg/kg) which was in good agreement with previous data reported in mice for another P-gp substrate (loperamide, ED₅₀: 5.7 mg/kg) [1]. Brain-to-plasma radioactivity ratios after 0 and 15 mg/kg of TQD were 0.23 and 3.15, respectively. Conclusion Our data suggest that TQD is a potent inhibitor of P-gp at the rat BBB. Moreover, VPM PET appears to be a useful tool for in vivo dose finding of novel P-gp inhibitors in animals and humans. [ABSTRACT FROM AUTHOR]