title: Chronic P-glycoprotein inhibition increases the brain concentration of escitalopram: potential implications for treating depression.
abstract: Recent preclinical studies have revealed a functionally important role for the drug efflux pump P-glycoprotein (P-gp) at the blood-brain barrier in limiting brain levels and thus antidepressant-like activity of certain antidepressant drugs. Specifically, acute administration of P-gp inhibitors, such as verapamil and cyclosporin A (CsA), has been shown to augment brain concentrations and functional activity of the antidepressant escitalopram in rodents. However, depression is a chronic disorder and current treatments require prolonged administration to elicit their full therapeutic effect. Thus, it is important to investigate whether acute findings in relation to P-gp inhibition translate to chronic paradigms. To this end, the present study investigates whether chronic treatment with the P-gp inhibitor verapamil and the antidepressant escitalopram results in enhanced brain distribution and antidepressant-like effects of escitalopram. Verapamil (10 mg·kg(-1) i.p.) and escitalopram (0.1 mg·kg(-1) i.p.) were administered once daily for 22 days. On the final day of treatment, brain regions and plasma were collected for analysis of cortical and plasma escitalopram concentrations, and to determine the hippocampal expression of genes previously reported to be altered by chronic antidepressant treatment. Verapamil treatment resulted in a greater than twofold increase in brain levels of escitalopram, without altering plasma levels. Neither gene expression analysis nor behavioral testing revealed an augmentation of responses to escitalopram treatment due to verapamil administration. Taken together, these data demonstrate for the first time that P-gp inhibition can yield elevated brain concentrations of an antidepressant after chronic treatment. The functional relevance of these increased brain levels requires further elaboration.
authors.affiliation: APC Microbiome Institute University College Cork CorkIreland; Pharmacodelivery Group School of Pharmacy University College Cork CorkIreland; Department of Anatomy & Neuroscience University College Cork CorkIreland; Present address: UCL School of Pharmacy University College London London United Kingdom.
authors.forename: Fionn E
authors.initials: FE
authors.lastname: O'Brien
authors.affiliation: Department of Anatomy & Neuroscience University College Cork Cork Ireland.
authors.forename: Gerard M
authors.initials: GM
authors.lastname: Moloney
authors.affiliation: Department of Anatomy & Neuroscience University College Cork Cork Ireland.
authors.forename: Karen A
authors.initials: KA
authors.lastname: Scott
authors.affiliation: Department of Anatomy & Neuroscience University College Cork Cork Ireland; Present address: Department of Pharmacology and Systems Therapeutics Icahn School of Medicine Mount Sinai Hospital NY USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: O'Connor
authors.affiliation: APC Microbiome Institute University College Cork Cork Ireland; Department of Psychiatry University College Cork Cork Ireland.
authors.forename: Gerard
authors.initials: G
authors.lastname: Clarke
authors.affiliation: APC Microbiome Institute University College Cork Cork Ireland; Department of Psychiatry University College Cork Cork Ireland.
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Dinan
authors.affiliation: Pharmacodelivery Group School of Pharmacy University College Cork Cork Ireland.
authors.forename: Brendan T
authors.initials: BT
authors.lastname: Griffin
authors.affiliation: APC Microbiome Institute University College Cork Cork Ireland; Department of Anatomy & Neuroscience University College Cork Cork Ireland.
authors.forename: John F
authors.initials: JF
authors.lastname: Cryan
keywords: Antidepressant; P‐glycoprotein; antidepressant augmentation; blood–brain barrier; escitalopram; treatment‐resistant depression