Aperçu: G.M.
Il
existe des preuves accumulées que le bumetanide, qui a été utilisé
pendant des décennies comme un diurétique puissant, exerce
également des effets sur les troubles du cerveau, y compris l'autisme,
les crises néonatales et l'épilepsie, qui ne sont liés à ses effets sur
le rein, mais plutôt médiés par l'inhibition du cotransporteur neuronal isoforme de Na-K-Cl, NKCC1.
Cependant,
suite à une administration systémique, les niveaux de bumétanide au
cerveau sont généralement inférieurs à ceux nécessaires pour inhiber le
NKCC1, ce qui limite considérablement son utilisation clinique pour
traiter les troubles du cerveau.La
compréhension des processus expliquant la pénétration médiocre du
cerveau dans le cerveau est nécessaire pour élaborer des stratégies pour
améliorer la transmission cérébrale de ce médicament.
Dans
la présente étude, des inhibiteurs probénécides
et plus sélectifs des transporteurs actifs au BBB ont été administrés directement dans le
cerveau des souris pour minimiser la contribution des effets
périphériques à la pénétration du bumetanide dans le cerveau .
Les
expériences in vivo ont démontré que l'absorption et l'efflux de
bumetanide au BBB sont beaucoup plus complexes qu'on ne le pensait
auparavant. Il
semble que la diffusion passive restreinte et le transport d'efflux
actif, médiés par l'Oat3, mais aussi le polypeptide organique de
transport d'anion (Oatp) Oatp1a4 et la protéine de résistance aux
multidrogènes 4, expliquent les concentrations de cerveau extrêmement
faibles qui sont obtenues après administration systémique du bumetanide, ce qui limite l'efficacité du traitement.
Neuropharmacology. 2017 Feb 10;117:182-194. doi: 10.1016/j.neuropharm.2017.02.006.
Multiple blood-brain barrier transport mechanisms limit bumetanide accumulation, and therapeutic potential, in the mammalian brain
Römermann K1, Fedrowitz M1, Hampel P2, Kaczmarek E1, Töllner K1, Erker T3, Sweet DH4, Löscher W5.
Author information
- 1
- Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany.
- 2
- Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany.
- 3
- Department of Medicinal Chemistry, University of Vienna, Vienna, Austria.
- 4
- Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA, USA.
- 5
- Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany. Electronic address: wolfgang.loescher@tiho-hannover.de
Abstract
There
is accumulating evidence that bumetanide, which has been used over
decades as a potent loop diuretic, also exerts effects on brain
disorders, including autism, neonatal seizures, and epilepsy, which are
not related to its effects on the kidney but rather mediated by
inhibition of the neuronal Na-K-Cl cotransporter isoform NKCC1. However,
following systemic administration, brain levels of bumetanide are
typically below those needed to inhibit NKCC1, which critically limits
its clinical use for treating brain disorders. Recently, active efflux
transport at the blood-brain barrier (BBB) has been suggested as a
process involved in the low brain:plasma ratio of bumetanide, but it is
presently not clear which transporters are involved. Understanding the
processes explaining the poor brain penetration of bumetanide is needed
for developing strategies to improve the brain delivery of this drug. In
the present study, we administered probenecid and more selective
inhibitors of active transport carriers at the BBB directly into the
brain of mice to minimize the contribution of peripheral effects on the
brain penetration of bumetanide. Furthermore, in vitro experiments with
mouse organic anion transporter 3 (Oat3)-overexpressing Chinese hamster
ovary cells were performed to study the interaction of bumetanide,
bumetanide derivatives, and several known inhibitors of Oats on
Oat3-mediated transport. The in vivo experiments demonstrated that the
uptake and efflux of bumetanide at the BBB is much more complex than
previously thought. It seems that both restricted passive diffusion and
active efflux transport, mediated by Oat3 but also organic
anion-transporting polypeptide (Oatp) Oatp1a4 and multidrug resistance
protein 4 explain the extremely low brain concentrations that are
achieved after systemic administration of bumetanide, limiting the use
of this drug for targeting abnormal expression of neuronal NKCC1 in
brain diseases.
Copyright © 2017 Elsevier Ltd. All rights reserved.
- PMID: 28192112
- DOI: 10.1016/j.neuropharm.2017.02.006
