pgp - publications

Predict more pgp - ligand interactions now!



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


Neuropsychopharmacology. 2013 May 14;


Authors: O'Brien FE, O'Connor RM, Clarke G, Dinan TG, Griffin BT, Cryan JF


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. Microdialysis-based pharmacokinetic studies demonstrated that administration of a P-gp inhibitor 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 a P-gp inhibitor 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 sub-therapeutic 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.Neuropsychopharmacology accepted article preview online, 14 May 2013; doi:10.1038/npp.2013.120.

PMID: 23670590 [PubMed - as supplied by publisher]