P-glycoprotein inhibition as a strategy to increase drug delivery across the blood-brain barrier: focus on antidepressants

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dc.contributor.advisorCryan, John F.en
dc.contributor.advisorGriffin, Brendan T.en
dc.contributor.authorO'Brien, Fionn E.
dc.date.accessioned2014-02-19T16:09:23Z
dc.date.available2014-02-19T16:09:23Z
dc.date.issued2013
dc.date.submitted2013
dc.description.abstractDepression is among the leading causes of disability worldwide. Currently available antidepressant drugs have unsatisfactory efficacy, with up to 60% of depressed patients failing to respond adequately to treatment. Emerging evidence has highlighted a potential role for the efflux transporter P-glycoprotein (P-gp), expressed at the blood-brain barrier (BBB), in the aetiology of treatment-resistant depression. In this thesis, the potential of P-gp inhibition as a strategy to enhance the brain distribution and pharmacodynamic effects of antidepressant drugs was investigated. Pharmacokinetic studies demonstrated that administration of the P-gp inhibitors verapamil or cyclosporin A (CsA) enhanced the BBB transport of the antidepressants imipramine and escitalopram in vivo. Furthermore, both imipramine and escitalopram were identified as transported substrates of human P-gp in vitro. Contrastingly, human P-gp exerted no effect on the transport of four other antidepressants (amitriptyline, duloxetine, fluoxetine and mirtazapine) in vitro. Pharmacodynamic studies revealed that pre-treatment with verapamil augmented the behavioural effects of escitalopram in the tail suspension test (TST) of antidepressant-like activity in mice. Moreover, pre-treatment with CsA exacerbated the behavioural manifestation of an escitalopram-induced mouse model of serotonin syndrome, a serious adverse reaction associated with serotonergic drugs. This finding highlights the potential for unwanted side-effects which may occur due to increasing brain levels of antidepressants by P-gp inhibition, although further studies are needed to fully elucidate the mechanism(s) at play. Taken together, the research outlined in this thesis indicates that P-gp may restrict brain concentrations of escitalopram and imipramine in patients. Moreover, we show that increasing the brain distribution of an antidepressant by P-gp inhibition can result in an augmentation of antidepressant-like activity in vivo. These findings raise the possibility that P-gp inhibition may represent a potentially beneficial strategy to augment antidepressant treatment in clinical practice. Further studies are now warranted to evaluate the safety and efficacy of this approach.en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationO'Brien, F. E. 2013. P-glycoprotein inhibition as a strategy to increase drug delivery across the blood-brain barrier: focus on antidepressants. PhD Thesis, University College Cork.en
dc.identifier.urihttps://hdl.handle.net/10468/1400
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2013, Fionn E. O'Brienen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectAntidepressanten
dc.subjectBlood-brain barrieren
dc.subjectDrug deliveryen
dc.subjectP-glycoproteinen
dc.subjectTreatment-resistant depressionen
dc.thesis.opt-outfalse
dc.titleP-glycoprotein inhibition as a strategy to increase drug delivery across the blood-brain barrier: focus on antidepressantsen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD (Medicine and Health)en
ucc.workflow.supervisorj.cryan@ucc.ie
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