P-glycoprotein Inhibition Increases the Brain Distribution and Antidepressant-Like Activity of Escitalopram in Rodents

Abstract

Despite the clinical prevalence of the antidepressant escitalopram, over 30% of escitalopram-treated patients fail to respond to treatment. Recent gene association studies have highlighted a potential link between the drug efflux transporter P-glycoprotein (P-gp) and response to escitalopram. The present studies investigated pharmacokinetic and pharmacodynamic interactions between P-gp and escitalopram. In vitro bidirectional transport studies revealed that escitalopram is a transported substrate of human P-gp. Microdialysisbased pharmacokinetic studies demonstrated that administration of the P-gp inhibitor cyclosporin A resulted in increased brain levels of escitalopram without altering plasma escitalopram levels in the rat, thereby showing that P-gp restricts escitalopram transport across the blood-brain barrier (BBB) in vivo. The tail suspension test (TST) was carried out to elucidate the pharmacodynamic impact of P-gp inhibition on escitalopram effect in a mouse model of antidepressant activity. Pre-treatment with the P-gp inhibitor verapamil enhanced the response to escitalopram in the TST. Taken together, these data indicate that P-gp may restrict the BBB transport of escitalopram in humans, potentially resulting in subtherapeutic brain concentrations in certain patients. Moreover, by verifying that increasing escitalopram delivery to the brain by P-gp inhibition results in enhanced antidepressant-like activity, we suggest that adjunctive treatment with a P-gp inhibitor may represent a beneficial approach to augment escitalopram therapy in depression.

Human P-glycoprotein differentially affects antidepressant drug transport: relevance to blood–brain barrier permeability

“…However, to our knowledge, there were no data pertaining to human P-gp available for mirtazapine before the present study. In contrast, two studies have reported pharmacogenetic associations between ABCB1 SNPs and response to the SSRI escitalopram (Lin et al, 2011;Singh et al, 2012), and we have recently identified escitalopram as a transported substrate of human P-gp in the same in vitro model as used in the present study (O'Brien et al, 2013). In addition, the finding that amitriptyline, duloxetine and fluoxetine were not transported substrates of human P-gp in our in vitro bidirectional transport model may help to explain why no association was found between ABCB1 SNPs and response to these antidepressants in previous clinical studies (Roberts et al, 2002;Laika et al, 2006;Perlis et al, 2010).…”

“…In light of well-documented species differences in P-gp activity and substrate specificity (Yamazaki et al, 2001;Katoh et al, 2006;Baltes et al, 2007;Syvanen et al, 2009), it was vital that further experiments to confirm that mirtazapine is not a transported substrate of human P-gp be conducted to facilitate informed interpretation of these clinical studies. Moreover, we have also demonstrated that inhibition of P-gp enhances the brain distribution and antidepressant-like activity of escitalopram in rodents (O'Brien et al, 2013). In contrast, two studies have reported pharmacogenetic associations between ABCB1 SNPs and response to the SSRI escitalopram (Lin et al, 2011;Singh et al, 2012), and we have recently identified escitalopram as a transported substrate of human P-gp in the same in vitro model as used in the present study (O'Brien et al, 2013).…”

“…P-gp substrates enter the P-gp substrate-binding pocket (SBP) via portals that are open to the cytoplasm and the inner leaflet of the lipid bilayer. Uhr et al, 2000;Mahar Doan et al, 2002;Faassen et al, 2003;Grauer and Uhr, 2004;Uhr et al, 2007 H H Doan et al, 2002;Faassen et al, 2003;Clarke et al, 2009;O'Brien et al, 2012b 2008; Doran et al, 2005;Ejsing and Linnet, 2005;Clarke et al, 2009;Karlsson et al, 2010;Bundgaard et al, 2012;O'Brien et al, 2012bO'Brien et al, , 2013Karlsson et al, 2013), there has been a paucity of studies investigating whether these antidepressants are also transported substrates of human P-gp. This triggers a conformational change that sterically occludes transport of the substrate into the cytoplasm or the inner leaflet of the bilayer.…”

The effect of organic anion transporter 3 inhibitor probenecid on bumetanide levels in the brain: an integrated in vivo microdialysis study in the rat

“…In this study, we investigate the effect of oat3 inhibition, which represents a novel potential augmentation strategy, on brain levels of bumetanide. Previously, studies in our group and others have demonstrated the potential of efflux transporter inhibition at the BBB to increase brain levels of neuropsychopharmacological agents [36,37]. OAT3 can be inhibited by probenecid, penicillins and statins [31,38,39].…”

Reliability of In Vitro and In Vivo Methods for Predicting the Effect of P-Glycoprotein on the Delivery of Antidepressants to the Brain

“…K p,uu,brain of escitalopram is also lower than 0.1 without pretreatment of CSA, yet increase, (but below 0.33) with P-gp inhibition [86]. These microdialysis studies [16,81] suggest that for K p,uu,brain values determined by this method, the cut-off between BBB+ and BBB− may be even lower than 0.1.…”