TY - JOUR T1 - Modulation of P-glycoprotein at the Human Blood-Brain Barrier by Quinidine or Rifampin Treatment: A Positron Emission Tomography Imaging Study JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1795 LP - 1804 DO - 10.1124/dmd.114.058685 VL - 43 IS - 11 AU - Li Liu AU - Ann C. Collier AU - Jeanne M. Link AU - Karen B. Domino AU - David A. Mankoff AU - Janet F. Eary AU - Charles F. Spiekerman AU - Peng Hsiao AU - Anand K. Deo AU - Jashvant D. Unadkat Y1 - 2015/11/01 UR - http://dmd.aspetjournals.org/content/43/11/1795.abstract N2 - Permeability-glycoprotein (P-glycoprotein, P-gp), an efflux transporter at the human blood-brain barrier (BBB), is a significant obstacle to central nervous system (CNS) delivery of P-gp substrate drugs. Using positron emission tomography imaging, we investigated P-gp modulation at the human BBB by an approved P-gp inhibitor, quinidine, or the P-gp inducer, rifampin. Cerebral blood flow (CBF) and BBB P-gp activity were respectively measured by administration of 15O-water followed by 11C-verapamil. In a crossover design, healthy volunteers received quinidine and 11–29 days of rifampin treatment during different study periods. CBF and P-gp activity was measured in the absence (control; prior to quinidine treatment) and presence of P-gp modulation. At clinically relevant quinidine plasma concentrations, P-gp inhibition resulted in a 60% increase in 11C-radioactivity distribution across the human BBB as measured by the brain extraction ratio (ER) of 11C-radioactivity. Furthermore, the magnitude of BBB P-gp inhibition by quinidine was successfully predicted by a combination of in vitro and macaque data, but not by rat data. Although our findings demonstrated that quinidine did not completely inhibit P-gp at the human BBB, it has the potential to produce clinically significant CNS drug interactions with P-gp substrate drugs that exhibit a narrow therapeutic window and are significantly excluded from the brain by P-gp. Rifampin treatment induced systemic CYP3A metabolism of 11C-verapamil; however, it reduced the ER by 6%. Therefore, we conclude that rifampin, at its usual clinical dose, cannot be used to induce P-gp at the human BBB to a clinically meaningful extent and is unlikely to cause inadvertent BBB-inductive drug interactions. ER -