RT Journal Article
SR Electronic
T1 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
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 1192
OP 1192
VO 50
IS supplement 2
A1 Claudia Wagner
A1 Thomas Feurstein
A1 Rudolf Karch
A1 Martin Bauer
A1 Stephan Kopp
A1 Peter Chiba
A1 Kurt Kletter
A1 Markus Mueller
A1 Markus Zeitlinger
A1 Oliver Langer
YR 2009
UL http://jnm.snmjournals.org/content/50/supplement_2/1192.abstract
AB 1192 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.