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In addition, clinical experience shows that adjunctive treatment with the P\u2010gp inhibitor verapamil may improve the clinical outcome in TRD. Therefore, the present study aimed to investigate the effect of P\u2010gp inhibition on the transport of the tricyclic antidepressant imipramine and its active metabolite desipramine across the BBB.<\/jats:p><\/jats:sec><jats:sec><jats:title>EXPERIMENTAL APPROACH<\/jats:title><jats:p>Intracerebral microdialysis in rats was used to monitor brain levels of imipramine and desipramine following i.v. imipramine administration, with or without pretreatment with one of the P\u2010gp inhibitors verapamil or cyclosporin A (CsA). Plasma drug levels were also determined at regular intervals.<\/jats:p><\/jats:sec><jats:sec><jats:title>KEY RESULTS<\/jats:title><jats:p>Pretreatment with either verapamil or CsA resulted in significant increases in imipramine concentrations in the microdialysis samples, without altering imipramine plasma pharmacokinetics. Furthermore, pretreatment with verapamil, but not CsA, led to a significant elevation in plasma and brain levels of desipramine.<\/jats:p><\/jats:sec><jats:sec><jats:title>CONCLUSIONS AND IMPLICATIONS<\/jats:title><jats:p>The present study demonstrated that P\u2010gp inhibition enhanced the intracerebral concentration of imipramine , thus supporting the hypothesis that P\u2010gp activity restricts brain levels of certain antidepressants, including imipramine. These findings may help to explain reports of a beneficial response to adjunctive therapy with verapamil in TRD.<\/jats:p><\/jats:sec>","DOI":"10.1111\/j.1476-5381.2012.01858.x","type":"journal-article","created":{"date-parts":[[2012,1,17]],"date-time":"2012-01-17T19:41:05Z","timestamp":1326829265000},"page":"1333-1343","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Inhibition of P\u2010glycoprotein enhances transport of imipramine across the blood\u2013brain barrier: microdialysis studies in conscious freely moving 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