title: Pgp-mediated interaction between (R)-[11C]verapamil and tariquidar at the human blood-brain barrier: a comparison with rat data.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Bauer
authors.forename: M
authors.initials: M
authors.lastname: Zeitlinger
authors.forename: R
authors.initials: R
authors.lastname: Karch
authors.forename: P
authors.initials: P
authors.lastname: Matzneller
authors.forename: J
authors.initials: J
authors.lastname: Stanek
authors.forename: W
authors.initials: W
authors.lastname: Jäger
authors.forename: M
authors.initials: M
authors.lastname: Böhmdorfer
authors.forename: W
authors.initials: W
authors.lastname: Wadsak
authors.forename: M
authors.initials: M
authors.lastname: Mitterhauser
authors.forename: J P
authors.initials: JP
authors.lastname: Bankstahl
authors.forename: W
authors.initials: W
authors.lastname: Löscher
authors.forename: M
authors.initials: M
authors.lastname: Koepp
authors.forename: C
authors.initials: C
authors.lastname: Kuntner
authors.forename: M
authors.initials: M
authors.lastname: Müller
authors.forename: Oliver
authors.initials: O
authors.lastname: Langer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000187:drug effects*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002250:Carbon Radioisotopes; D004305:Dose-Response Relationship, Drug; D006801:Humans; D049268:Positron-Emission Tomography / Q000379:methods / Q000706:statistics & numerical data; D011804:Quinolines / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D013045:Species Specificity; D014700:Verapamil / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002121:Calcium Channel Blockers; D002250:Carbon Radioisotopes; D011804:Quinolines; D014700:Verapamil; C402343:tariquidar