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

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dc.contributor.advisor Cryan, John F. en
dc.contributor.advisor Griffin, Brendan T. en
dc.contributor.author O'Brien, Fionn E.
dc.date.accessioned 2014-02-19T16:09:23Z
dc.date.available 2014-02-19T16:09:23Z
dc.date.issued 2013
dc.date.submitted 2013
dc.identifier.citation O'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.uri http://hdl.handle.net/10468/1400
dc.description.abstract Depression 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.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2013, Fionn E. O'Brien en
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/3.0/ en
dc.subject Antidepressant en
dc.subject Blood-brain barrier en
dc.subject Drug delivery en
dc.subject P-glycoprotein en
dc.subject Treatment-resistant depression en
dc.title P-glycoprotein inhibition as a strategy to increase drug delivery across the blood-brain barrier: focus on antidepressants en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD (Medicine and Health) en
dc.internal.availability Full text available en
dc.check.info No embargo required en
dc.description.version Accepted Version
dc.description.status Not peer reviewed en
dc.internal.school Alimentary Pharmabotic Centre en
dc.internal.school Anatomy en
dc.internal.school Pharmacy en
dc.check.type No Embargo Required
dc.check.reason No embargo required en
dc.check.opt-out Not applicable en
dc.thesis.opt-out false
dc.check.embargoformat Not applicable en
ucc.workflow.supervisor j.cryan@ucc.ie
dc.internal.conferring Spring Conferring 2014 en

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© 2013, Fionn E. O'Brien Except where otherwise noted, this item's license is described as © 2013, Fionn E. O'Brien
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