title: Assessment of P-Glycoprotein Transport Activity at the Human Blood-Retina Barrier with (R)-11C-Verapamil PET.
abstract: P-glycoprotein (ABCB1) is expressed at the blood-retina barrier (BRB), where it may control distribution of drugs from blood to the retina and thereby influence drug efficacy and toxicity.Methods:We performed PET scans with the ABCB1 substrate (R)-11C-verapamil on 5 healthy male volunteers without and with concurrent infusion of the ABCB1 inhibitor tariquidar. We estimated the rate constants for radiotracer transfer across the BRB (K1,k2) and total retinal distribution volumeVTResults:During ABCB1 inhibition, retinalVTand influx rate constantK1were significantly, by 1.4 ± 0.5-fold and 1.5 ± 0.3-fold, increased compared with baseline. Retinal efflux rate constantk2was significantly decreased by 2.8 ± 1.0-fold.Conclusion:We found a significant increase in (R)-11C-verapamil distribution to the retina during ABCB1 inhibition, which provides first in vivo evidence for ABCB1 transport activity at the human BRB. The increase in retinal distribution was approximately 2.5-fold less pronounced than previously reported for the blood-brain barrier.
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Bauer
authors.affiliation: Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Karch
authors.affiliation: Imagerie Moléculaire In Vivo, IMIV, CEA, INSERM, CNRS, Université Paris-Sud, Université Paris Saclay, CEA-SHFJ, Orsay, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Tournier
authors.affiliation: Variabilité de Réponse aux Psychotropes, INSERM, U1144 and Faculté de Pharmacie, Université Paris Descartes, UMR-S 1144, Paris, France.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cisternino
authors.affiliation: Department of Biomedical Imaging und Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wadsak
authors.affiliation: Department of Biomedical Imaging und Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Marcus
authors.initials: M
authors.lastname: Hacker
authors.affiliation: Department of Anesthesiology, General Intensive Care, and Pain Medicine, Medical University of Vienna, Vienna, Austria; and.
authors.forename: Peter
authors.initials: P
authors.lastname: Marhofer
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Zeitlinger
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria oliver.langer@meduniwien.ac.at.|Department of Biomedical Imaging und Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, Vienna, Austria.|Health and Environment Department, AIT Austrian Institute of Technology GmbH, Seibersdorf, Austria.
authors.forename: Oliver
authors.initials: O
authors.lastname: Langer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000097:blood* / Q000378:metabolism*; D000328:Adult; D002250:Carbon Radioisotopes; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D049268:Positron-Emission Tomography; D021381:Protein Transport; D012160:Retina / Q000378:metabolism*; D014700:Verapamil
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002250:Carbon Radioisotopes; D014700:Verapamil
keywords: P-glycoprotein; PET; blood–brain barrier; blood–retina barrier; eye