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 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, +24% +/- 15%) and influx rate constant (K(1), +49% +/- 36%) of (R)-(11)C-verapamil across the BBB (DV, 0.65 +/- 0.13 and 0.80 +/- 0.07, P = 0.043; K(1), 0.034 +/- 0.009 and 0.049 +/- 0.009, P = 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 = 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.


CONCLUSIONS
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.
Wagner
Claudia C
CC
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
Bauer
Martin
M
Karch
Rudolf
R
Feurstein
Thomas
T
Kopp
Stephan
S
Chiba
Peter
P
Kletter
Kurt
K
Löscher
Wolfgang
W
Müller
Markus
M
Zeitlinger
Markus
M
Langer
Oliver
O
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000328:Adult; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging* / Q000187:drug effects / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D008297:Male; D010865:Pilot Projects; D049268:Positron-Emission Tomography; D011804:Quinolines / Q000494:pharmacology*; D014700:Verapamil / Q000737:chemistry / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002250:Carbon Radioisotopes; D011804:Quinolines; D014700:Verapamil; C402343:tariquidar