Pgp-mediated interaction between (R)-[11C]verapamil and tariquidar at the human blood-brain barrier: a comparison with rat data

• Published in: Clinical pharmacology and therapeutics Vol. 91; no. 2; p. 227
• Main Authors: Bauer, M, Zeitlinger, M, Karch, R, Matzneller, P, Stanek, J, Jäger, W, Böhmdorfer, M, Wadsak, W, Mitterhauser, M, Bankstahl, J P, Löscher, W, Koepp, M, Kuntner, C, Müller, M, Langer, Oliver
• Format: Journal Article
• Language: English
• Published: United States 01.02.2012
• Subjects: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; Blood-Brain Barrier - diagnostic imaging; Blood-Brain Barrier - drug effects; Brain - diagnostic imaging; Brain - metabolism; Calcium Channel Blockers - pharmacology; Carbon Radioisotopes; Dose-Response Relationship, Drug; Humans; Positron-Emission Tomography - methods; Positron-Emission Tomography - statistics & numerical data; Quinolines - blood; Quinolines - pharmacology; Rats; Species Specificity; Verapamil - pharmacokinetics
• DOI: 10.1038/clpt.2011.217

Using positron emission tomography (PET) imaging we assessed, in vivo, the interaction between a microdose of (R)-[(11)C]verapamil (a P-glycoprotein (Pgp) substrate) and escalating doses of the Pgp inhibitor tariquidar (3, 4, 6, and 8 mg/kg) at the blood-brain barrier (BBB) in healthy human subjects. We compared the dose-response relationship of tariquidar in humans with data obtained in rats using a similar methodology. Tariquidar was equipotent in humans and rats in its effect of increasing (R)-[(11)C]verapamil brain uptake (expressed as whole-brain volume of distribution (V(T))), with very similar half-maximum-effect concentrations. Both in humans and in rats, brain V(T) approached plateau levels at plasma tariquidar concentrations >1,000 ng/ml. However, Pgp inhibition in humans led to only a 2.7-fold increase in brain V(T) relative to baseline scans (before administration of tariquidar) as compared with 11.0-fold in rats. The results of this translational study add to the accumulating evidence that there are marked species-dependent differences in Pgp expression and functionality at the BBB.