TY - JOUR
T1 - Modulation of P-glycoprotein at the human blood-brain barrier by quinidine or rifampin treatment
T2 - A positron emission tomography imaging study
AU - Liu, Li
AU - Collier, Ann C.
AU - Link, Jeanne M.
AU - Domino, Karen B.
AU - Mankoff, David A.
AU - Eary, Janet F.
AU - Spiekerman, Charles F.
AU - Hsiao, Peng
AU - Deo, Anand K.
AU - Unadkat, Jashvant D.
N1 - Publisher Copyright:
Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2015/11/1
Y1 - 2015/11/1
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.
AB - 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.
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U2 - 10.1124/dmd.114.058685
DO - 10.1124/dmd.114.058685
M3 - Article
C2 - 26354948
AN - SCOPUS:84946210010
SN - 0090-9556
VL - 43
SP - 1795
EP - 1804
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
IS - 11
ER -