Modulation of P-glycoprotein at the Human Blood-Brain Barrier by Quinidine or Rifampin Treatment: A Positron Emission Tomography Imaging Study.
Drug Metab Dispos
; 43(11): 1795-804, 2015 Nov.
Article
en En
| MEDLINE
| ID: mdl-26354948
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 (15)O-water followed by (11)C-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 (11)C-radioactivity distribution across the human BBB as measured by the brain extraction ratio (ER) of (11)C-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 (11)C-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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Quinidina
/
Rifampin
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Barrera Hematoencefálica
/
Miembro 1 de la Subfamilia B de Casetes de Unión a ATP
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Tomografía de Emisión de Positrones
Tipo de estudio:
Clinical_trials
/
Prognostic_studies
Límite:
Adult
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Animals
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Female
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Humans
/
Male
Idioma:
En
Revista:
Drug Metab Dispos
Asunto de la revista:
FARMACOLOGIA
Año:
2015
Tipo del documento:
Article