title: A Prediction Method for P-glycoprotein-Mediated Drug-Drug Interactions at the Human Blood-Brain Barrier From Blood Concentration-Time Profiles, Validated With PET Data.
abstract: The purpose of this study was to establish physiologically based pharmacokinetic models to predict in humans the brain concentration-time profiles and P-glycoprotein (Pgp)-mediated brain drug-drug interactions between the model Pgp substrate (R)-[11C]verapamil (VPM), the model dual Pgp/breast cancer resistance protein (BCRP) substrate [11C]tariquidar (TQD), and the Pgp inhibitor tariquidar. The model predictions were validated with results from positron emission tomography studies in humans. Using these physiologically based pharmacokinetic models, the differences between predicted and observed areas under the concentration-time curves (AUC) of VPM and TQD in the brain were within a 1.2-fold and 2.5-fold range, respectively. Also, brain AUC increases of VPM and TQD after Pgp inhibitor administration were predicted with 2.5-fold accuracy when in vitro inhibition constant or half-maximum inhibitory concentration values of tariquidar were used. The predicted rank order of the magnitude of AUC increases reflected the results of the clinical positron emission tomography studies. Our results suggest that the established models can predict brain exposure from the respective blood concentration-time profiles and rank the magnitude of the Pgp-mediated brain drug-drug interaction potential for both Pgp and Pgp/BCRP substrates in humans.
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Matsuda
authors.affiliation: Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, A-1090 Vienna, Austria.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Karch
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Bauer
authors.affiliation: Center for Health and Bioresources, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Traxl
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Zeitlinger
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria; Center for Health and Bioresources, AIT Austrian Institute of Technology GmbH, A-2444 Seibersdorf, Austria; Department of Biomedical Imaging and Image-Guided Therapy, Division of Nuclear Medicine, Medical University of Vienna, A-1090 Vienna, Austria. Electronic address: oliver.langer@meduniwien.ac.at.
authors.forename: Oliver
authors.initials: O
authors.lastname: Langer
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000378:metabolism; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects; D003198:Computer Simulation; D004347:Drug Interactions; D006801:Humans; D008954:Models, Biological; D009363:Neoplasm Proteins / Q000378:metabolism; D049268:Positron-Emission Tomography; D011804:Quinolines / Q000493:pharmacokinetics* / Q000494:pharmacology; D014700:Verapamil / Q000493:pharmacokinetics*
chemical_list: C116614:ABCG2 protein, human; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D000889:Anti-Arrhythmia Agents; D009363:Neoplasm Proteins; D011804:Quinolines; D014700:Verapamil; C402343:tariquidar
keywords: ABC transporters; P-glycoprotein; PET; blood–brain barrier; drug-drug interactions; physiologically based pharmacokinetic model