title: 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. Microdialysis-based 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.
authors.affiliation: 1] Alimentary Pharmabiotic Center, University College Cork, Cork, Ireland [2] Pharmacodelivery Group, School of Pharmacy, University College Cork, Cork, Ireland [3] Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
authors.forename: Fionn E
authors.initials: FE
authors.lastname: O'Brien
authors.forename: Richard M
authors.initials: RM
authors.lastname: O'Connor
authors.forename: Gerard
authors.initials: G
authors.lastname: Clarke
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Dinan
authors.forename: Brendan T
authors.initials: BT
authors.lastname: Griffin
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000187:drug effects; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000493:pharmacokinetics / Q000494:pharmacology; D001693:Biological Transport, Active / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000378:metabolism*; D015283:Citalopram / Q000493:pharmacokinetics* / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology; D004285:Dogs; D004347:Drug Interactions; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D051379:Mice; D051381:Rats; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018687:Antidepressive Agents, Second-Generation; D015283:Citalopram; D016572:Cyclosporine; D014700:Verapamil