Modulation of P-glycoprotein at the human blood-brain barrier by quinidine or rifampin treatment: A positron emission tomography imaging study

Li Liu, Ann C. Collier, Jeanne M. Link, Karen B. Domino, David A. Mankoff, Janet F. Eary, Charles F. Spiekerman, Peng Hsiao, Anand K. Deo, Jashvant D. Unadkat

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38 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1795-1804
Number of pages10
JournalDrug Metabolism and Disposition
Issue number11
StatePublished - Nov 1 2015
Externally publishedYes

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science


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