Premium
Role of drug efflux carriers in the healthy and diseased brain
Author(s) -
Hermann Dirk M.,
Kilic Ertugrul,
Spudich Annett,
Krämer Stefanie D.,
WunderliAllenspach Heidi,
Bassetti Claudio L.
Publication year - 2006
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.21012
Subject(s) - efflux , pharmacology , blood–brain barrier , drug , transporter , atp binding cassette transporter , downregulation and upregulation , neuroprotection , medicine , epilepsy , solute carrier family , chemistry , biology , neuroscience , central nervous system , biochemistry , gene
The blood–brain barrier is a natural diffusion barrier, which expresses active carriers extruding drugs on their way to the brain back into the blood against concentration gradients. Whereas these so‐called adenosine triphosphate–binding cassette (ABC) transporters prevent the brain entry of toxic compounds under physiological conditions, they complicate pharmacotherapies in neurological disease. Recent observations in animal models of ischemic stroke, drug‐resistant epilepsy, and brain cancer showed that the prototype of ABC transporters, ABCB1, is upregulated on brain injury, deactivation of this carrier considerably enhancing the accumulation of neuroprotective, antiepileptic, and chemotherapeutic compounds. These studies provide the proof of concept that the efficacy of brain‐targeting drugs may significantly be improved when drug efflux is blocked. Under clinical conditions, efforts currently are made to enhance drug accumulation by selecting new compounds that do not bind to efflux carriers or deactivating ABC transporters by targeted downregulation or pharmacological inhibition. We predict that strategies aiming at circumventing drug efflux may greatly facilitate progress in neurological therapies. Ann Neurol 2006