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In vitro bidirectional permeability studies identify pharmacokinetic limitations of NKCC1 inhibitor bumetanide

Overview of attention for article published in European Journal of Pharmacology, January 2016
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Title
In vitro bidirectional permeability studies identify pharmacokinetic limitations of NKCC1 inhibitor bumetanide
Published in
European Journal of Pharmacology, January 2016
DOI 10.1016/j.ejphar.2015.12.001
Pubmed ID
Authors

Maria D. Donovan, Harriët Schellekens, Geraldine B. Boylan, John F. Cryan, Brendan T. Griffin

Abstract

Recently, it has been suggested that bumetanide, an inhibitor of the Na-K-2Cl co-transporter (NKCC1), may be useful in the treatment of central nervous system (CNS) disorders. However, from a physicochemical perspective, bumetanide may not cross the blood-brain barrier to the extent that is necessary for it to be an effective brain NKCC1 inhibitor in vivo. High plasma-protein binding, potentially high brain-tissue binding and putative efflux transporters including organic anion transporter 3 (OAT3) contribute to the poor pharmacokinetic profile of bumetanide. Bidirectional permeability assays are an in vitro method to determine the impact of plasma-protein/brain tissue binding, as well as efflux transport, on the permeability of a compound. We established and validated a cell line stably overexpressing human OAT3 using lentiviral cloning techniques for use in in vitro bidirectional permeability assays. Using efflux transport studies, we show that bumetanide is a transported substrate of human OAT3, exhibiting a transport ratio of ≥1.5, which is attenuated by OAT3 inhibitors. Bidirectional permeability assays were carried out in the presence and absence of either albumin or brain homogenate to elucidate the effect of plasma-protein/brain tissue binding. These tests confirmed the pharmacokinetic limitations for brain delivery of bumetanide. In this experiment, bumetanide is 53% bound to albumin, 77% bound to brain tissue and accumulates in brain cells. Moreover, we conclusively established that bumetanide is a transported substrate of OAT3. Taken together, these bidirectional permeability studies highlight the potential of efflux transporter inhibition as an augmentation strategy for enhanced delivery of bumetanide to the CNS.

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Mendeley readers

The data shown below were compiled from readership statistics for 26 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Germany 1 4%
Unknown 25 96%

Demographic breakdown

Readers by professional status Count As %
Student > Master 5 19%
Student > Bachelor 4 15%
Researcher 3 12%
Professor 3 12%
Student > Doctoral Student 1 4%
Other 4 15%
Unknown 6 23%
Readers by discipline Count As %
Medicine and Dentistry 5 19%
Agricultural and Biological Sciences 4 15%
Neuroscience 4 15%
Psychology 3 12%
Pharmacology, Toxicology and Pharmaceutical Science 1 4%
Other 1 4%
Unknown 8 31%

Attention Score in Context

This research output has an Altmetric Attention Score of 1. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 13 August 2017.
All research outputs
#9,773,682
of 12,231,598 outputs
Outputs from European Journal of Pharmacology
#5,001
of 5,834 outputs
Outputs of similar age
#195,720
of 267,820 outputs
Outputs of similar age from European Journal of Pharmacology
#17
of 44 outputs
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We're also able to compare this research output to 44 others from the same source and published within six weeks on either side of this one. This one is in the 43rd percentile – i.e., 43% of its contemporaries scored the same or lower than it.