Abstract
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.
Footnotes
- Received May 14, 2014.
- Accepted September 1, 2015.
This work was supported by the National Institutes of Health [Grants RCNS06804 and GM032165] and the National Center For Advancing Translational Sciences of the National Institutes of Health [Award Number UL1TR000423]. Li Liu was supported in part by the TL1 Multidisciplinary Predoctoral Clinical Research Training Program.
- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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