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      ABCB1 polymorphism predicts escitalopram dose needed for remission in major depression

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          Abstract

          The ATP-binding cassette family of transporter proteins, subfamily B (MDR/TAP), member 1 (ABCB1) (P-glycoprotein) transporter is a key component of the blood–brain barrier. Many antidepressants are subject to ABCB1 efflux. Functional polymorphisms of ABCB1 may influence central nervous system bioavailability of antidepressants subject to efflux. Single-nucleotide polymorphisms (SNPs) at rs1045642 (C3435T) of ABCB1 have been associated with efflux pump efficiency. This may explain part of the interindividual variation in antidepressant dose needed to remit. Individuals ( N=113) with DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) major depressive disorder (MDD) were treated with escitalopram (ESC) or venlafaxine (VEN) over 8 weeks. The17-item Hamilton Depression Rating Scale was assessed serially, blind to genotype. SNP rs1045642 of ABCB1 along with two SNPs previously reported to be in linkage disequilibrium with it (rs2032582 and rs1128503) were genotyped. Demographic features, clinical features, P450 metabolizer status and 5-HTTLPR (serotonin-transporter-linked promoter region) genotype were controlled for. Carriers of rs1045642 TT needed on average 11 mg of ESC to remit, whereas TC and CC carriers required 24 and 19 mg, respectively ( P=0.0001). This equates to a 2.0- (95% confidence interval=1.5–3.4; P<0.001) fold greater ESC dose needed to remit for C carriers compared with TT carriers at rs1045642. Of VEN-treated subjects carrying TT genotype at rs1045642, 73.3% remitted compared with 12.5% for CC genotype (odds ratio=6.69; 95% confidence interval=1.72–25.9, P=0.006). These data suggest that antidepressant dose needed to remit can be predicted by an ABCB1 SNP. This has the potential clinical translation implications for dose selection and remission from MDD.

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          Most cited references33

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          A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants.

          Chinese hamster ovary cells selected for resistance to colchicine display pleiotropic cross-resistance to a wide range of amphiphilic drugs. The drug-resistant phenotype is due to a membrane alteration which reduces the rate of drug permeation. Surface labelling studies reveal that drug-resistant Chinese hamster ovary cell membranes possess a carbohydrate-containing component of 170 000 daltons apparent molecular weight which is not observed in wild type cells. Through studies of the metabolic incorporation of carbohydrate and protein precursors, and through the use of selective proteolysis, this component is shown to be a cell surface glycoprotein. Since this glycoprotein appears unique to mutant cells displaying altered drug permeability, we have designated it the P glycoprotein. The relative amount of surface labelled P glycoprotein correlates with the degree of drug resistance in a number of independent mutant and revertant clones. A similar high molecular weight glycoprotein is also present in drug-resistant mutants from another hamster cell line. Observations on the molecular basis of pleiotropic drug resistance are interpreted in terms of a model wherein certain surface glycoproteins control drug permeation by modulating the properties of hydrophobic membrane regions...
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            Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo.

            To evaluate whether alterations in the multidrug-resistance (MDR)-1 gene correlate with intestinal MDR-1 expression and uptake of orally administered P-glycoprotein (PGP) substrates, we analyzed the MDR-1 sequence in 21 volunteers whose PGP expression and function in the duodenum had been determined by Western blots and quantitative immunohistology (n = 21) or by plasma concentrations after orally administered digoxin (n = 8 + 14). We observed a significant correlation of a polymorphism in exon 26 (C3435T) of MDR-1 with expression levels and function of MDR-1. Individuals homozygous for this polymorphism had significantly lower duodenal MDR-1 expression and the highest digoxin plasma levels. Homozygosity for this variant was observed in 24% of our sample population (n = 188). This polymorphism is expected to affect the absorption and tissue concentrations of numerous other substrates of MDR-1.
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              P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs.

              The mouse mdr1a (also called mdr3) P-GP is abundant in the blood-brain barrier, and its absence in mdr1a (-/-) mice leads to highly increased levels of the drugs ivermectin, vinblastine, digoxin, and cyclosporin A in the brain. We show here that the drugs loperamide, domperidone, and ondansetron are transported substrates for the mouse mdr1a P-GP and its human homologue MDR1. Phenytoin is a relatively weaker substrate for each, and the drugs haloperidol, clozapine, and flunitrazepam are transported hardly or not at all. Tissue distribution studies demonstrated that the relative brain penetration of radiolabeled ondansetron and loperamide (and their metabolites) is increased four- and sevenfold, respectively, in mdr1a (-/-) mice. A pilot toxicity study with oral loperamide showed that this peripherally acting antidiarrheal agent gains potent opiatelike activity in the central nervous system of mdr1a (-/-) mice. mdr1a (-/-) mice also showed increased sensitivity to neurolepticlike side effects of oral domperidone. These results point to the possible role that the drug-transporting P-GP(s) may play in the clinical use of many drugs, especially those with potential targets in the central nervous system.
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                Author and article information

                Journal
                Transl Psychiatry
                Transl Psychiatry
                Translational Psychiatry
                Nature Publishing Group
                2158-3188
                November 2012
                27 November 2012
                1 November 2012
                : 2
                : 11
                : e198
                Affiliations
                [1 ]School of Medicine, Deakin University , Geelong, VIC, Australia
                [2 ]Department of Psychiatry, The University of Melbourne , Parkville, VIC, Australia
                [3 ]Department of General Practice, The University of Melbourne , Parkville, VIC, Australia
                [4 ]Swinburne University of Technology, Centre for Human Psychopharmacology , Hawthorne, VIC, Australia
                [5 ]Florey Institute of Neuroscience and Mental Health , Parkville, VIC, Australia
                [6 ]Healthscope Pathology , Clayton, VIC, Australia
                [7 ]Orygen Youth Health Research Centre, Centre for Youth Mental Health , Parkville, VIC, Australia
                Author notes
                [* ]School of Medicine, Deakin University , PO Box 9148, St Albans Park, Geelong, VIC, 3219 Australia. E-mail: a.singh@ 123456deakin.edu.au
                Article
                tp2012115
                10.1038/tp.2012.115
                3565756
                23188198
                b07459e8-7655-4603-b759-0a2317f9a088
                Copyright © 2012 Macmillan Publishers Limited

                This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/

                History
                : 12 September 2012
                : 06 October 2012
                Categories
                Original Article

                Clinical Psychology & Psychiatry
                abcb1,blood–brain barrier,antidepressant,pharmacogenetics,p-glycoprotein,major depression

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