Role of drug efflux carriers in the healthy and diseased brain.
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.
Hermann
Dirk M
DM
Department of Neurology, University Hospital Zurich, Switzerland.
Kilic
Ertugrul
E
Department of Neurology, University Hospital Zurich, Switzerland.
Spudich
Annett
A
Department of Neurology, University Hospital Zurich, Switzerland.
Krämer
Stefanie D
SD
Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland.
Wunderli-Allenspach
Heidi
H
Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland.
Bassetti
Claudio L
CL
Department of Neurology, University Hospital Zurich, Switzerland.
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D001927:Brain Diseases / Q000378:metabolism* / Q000503:physiopathology; D003986:Dibenzocycloheptenes / Q000493:pharmacokinetics; D015658:HIV Infections / Q000134:cerebrospinal fluid / Q000821:virology; D006801:Humans; D020925:Hypoxia-Ischemia, Brain / Q000378:metabolism / Q000503:physiopathology; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D010599:Pharmacokinetics; D011804:Quinolines / Q000493:pharmacokinetics; D015854:Up-Regulation
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D003986:Dibenzocycloheptenes; D027361:Organic Anion Transporters; D011804:Quinolines; C095179:zosuquidar trihydrochloride