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Exploring the possible interaction between anti-epilepsy drugs and multidrug efflux pumps; in vitro observations

Rivers, Francesca; O'Brien, Terence J.; Callaghan, Richard

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Approximately one-third of patients with epilepsy display an inherent resistance to pharmacological therapy, manifest as continuing seizures despite maximal tolerated doses of anti-epileptic drugs. One hypothesis for the underlying mechanism of anti-epileptic drug pharmacoresistance is lower drug entry to the epileptic neurones due to the activity of multidrug efflux pumps from the ATP Binding Cassette (ABC) superfamily at the blood-brain barrier. There has been a steady accumulation of animal...[Show more]

dc.contributor.authorRivers, Francesca
dc.contributor.authorO'Brien, Terence J.
dc.contributor.authorCallaghan, Richard
dc.date.accessioned2015-12-13T22:17:28Z
dc.identifier.issn0014-2999
dc.identifier.urihttp://hdl.handle.net/1885/71148
dc.description.abstractApproximately one-third of patients with epilepsy display an inherent resistance to pharmacological therapy, manifest as continuing seizures despite maximal tolerated doses of anti-epileptic drugs. One hypothesis for the underlying mechanism of anti-epileptic drug pharmacoresistance is lower drug entry to the epileptic neurones due to the activity of multidrug efflux pumps from the ATP Binding Cassette (ABC) superfamily at the blood-brain barrier. There has been a steady accumulation of animal and human data supporting this theory, particularly for ABCB1 (P-glycoprotein). However, much of this evidence is indirect. In the present study, several anti-epileptic drugs (carbamazepine, valproic acid, phenytoin, lamotrigine and primidone) were examined for their ability to interact with three ABC transporters that have been implicated pharmacoresistance of anti-epileptic drugs - ABCB1, ABCC1 and ABCG2. Interaction of anti-epileptic drugs with the transporters was assessed by determining whether they could reverse the ability of multidrug ABC transporters to confer a drug resistance phenotype on cancer cell lines. None of these compounds was able to affect the phenotype, suggesting an absence of any interaction with the multidrug transporters. This finding was further investigated by examination of transporter activity; namely the ability to reduce steady-state intracellular [3H]-radiolabelled drug accumulation. None of the anti-epileptic drugs affected labelled drug accumulation by any of the triumvirate of multidrug transporters examined, indicating that they are unlikely to be substrates. The lack of direct modulation by anti-epileptic drugs of ABC transporter function suggests that these proteins do not contribute significantly to resistance in epilepsy.
dc.publisherElsevier
dc.sourceEuropean Journal of Pharmacology
dc.subjectKeywords: ABC transporter; anticonvulsive agent; breast cancer resistance protein; carbamazepine; glycoprotein P; lamotrigine; multidrug resistance protein 1; phenytoin; primidone; valproic acid; article; blood brain barrier; cancer cell culture; drug accumulation; ABC transporter; ABCB1; ABCC1; ABCG2; Anti-epileptic drugs; Drug resistance; Epilepsy; Multidrug efflux
dc.titleExploring the possible interaction between anti-epilepsy drugs and multidrug efflux pumps; in vitro observations
dc.typeJournal article
local.description.notesImported from ARIES
local.identifier.citationvolume598
dc.date.issued2008
local.identifier.absfor060199 - Biochemistry and Cell Biology not elsewhere classified
local.identifier.absfor060110 - Receptors and Membrane Biology
local.identifier.absfor060112 - Structural Biology (incl. Macromolecular Modelling)
local.identifier.ariespublicationU3488905xPUB2578
local.type.statusPublished Version
local.contributor.affiliationRivers, Francesca, University of Oxford
local.contributor.affiliationO'Brien, Terence J., The University of Melbourne
local.contributor.affiliationCallaghan, Richard, College of Medicine, Biology and Environment, ANU
local.description.embargo2037-12-31
local.bibliographicCitation.issue1-3
local.bibliographicCitation.startpage1
local.bibliographicCitation.lastpage8
local.identifier.doi10.1016/j.ejphar.2008.09.014
local.identifier.absseo970106 - Expanding Knowledge in the Biological Sciences
dc.date.updated2015-12-11T07:34:28Z
local.identifier.scopusID2-s2.0-54149093975
CollectionsANU Research Publications

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