Abstract
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Objectives Tariquidar (TQD), a potent, nontoxic, third-generation P-glycoprotein (P-gp) inhibitor, is a possible reversal agent for central nervous system drug resistance. In animal studies, TQD 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 TQD administration using PET and the model P-gp substrate (R)–[11C]verapamil (VPM).
Methods 5 healthy volunteers underwent paired VPM PET scans and arterial blood sampling, before and at 3 h after i.v. administration of TQD (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.
Results TQD administration resulted in significant increases (paired t-test) in the distribution volume (DV) and influx rate constant (K1) of VPM across the BBB (DV= 0.64±0.12 and 0.79±0.07, p=0.012; K1=0.034±0.01 and 0.049±0.01, p=0.024, before and after TQD, respectively). A strong correlation was observed between TQD exposure in plasma and change in brain DV after administration of TQD (r=0.932, p=0.021). The administered dose of TQD resulted in 100% inhibition of P-gp function in peripheral lymphocytes.
Conclusions TQD significantly increased brain penetration of VPM, due to increased influx. As opposed to peripheral P-gp function, central P-gp inhibition appeared to be far from complete after the administered TQD dose.
- © 2009 by Society of Nuclear Medicine