P-glycoprotein inhibition as a strategy to increase drug delivery across the blood-brain barrier: focus on antidepressants
Contribuinte(s) |
Cryan, John F. Griffin, Brendan T. |
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Data(s) |
19/02/2014
19/02/2014
2013
2013
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Resumo |
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. Accepted Version Not peer reviewed |
Formato |
application/pdf |
Identificador |
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. |
Idioma(s) |
en en |
Publicador |
University College Cork |
Direitos |
© 2013, Fionn E. O'Brien http://creativecommons.org/licenses/by-nc-nd/3.0/ |
Palavras-Chave | #Antidepressant #Blood-brain barrier #Drug delivery #P-glycoprotein #Treatment-resistant depression |
Tipo |
Doctoral thesis Doctoral PhD (Medicine and Health) |