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However, the expression of<jats:styled-content style=\"fixed-case\">BRB<\/jats:styled-content>transporters and their quantitative impact<jats:italic>in vivo<\/jats:italic>are still poorly understood.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>Clonidine and diphenhydramine are substrates of a novel<jats:styled-content style=\"fixed-case\">BBB<\/jats:styled-content>drug\/proton\u2010antiporter. We evaluated their transport at the<jats:styled-content style=\"fixed-case\">BRB<\/jats:styled-content>by<jats:italic>in situ<\/jats:italic>carotid perfusion in wild\u2010type or knocked\u2010out mice for<jats:styled-content style=\"fixed-case\">O<\/jats:styled-content>ct1\u20103 (<jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>lc22a1\u20103).<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>At pharmacological exposure levels, carrier\u2010mediated<jats:styled-content style=\"fixed-case\">BRB<\/jats:styled-content>influx was 2 and 12 times greater than the passive diffusion rate for clonidine and diphenhydramine, respectively. Functional identification demonstrated the involvement of a high\u2010capacity potassium\u2010 and sodium\u2010independent proton\u2010antiporter that shared the features of the previously characterized clonidine, diphenhydramine and cocaine<jats:styled-content style=\"fixed-case\">BBB<\/jats:styled-content>transporter. The functional characterization suggests that<jats:styled-content style=\"fixed-case\">SLC<\/jats:styled-content>transporters<jats:styled-content style=\"fixed-case\">O<\/jats:styled-content>ct1\u20103,<jats:styled-content style=\"fixed-case\">M<\/jats:styled-content>ate1 (<jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>lc47a1) and<jats:styled-content style=\"fixed-case\">O<\/jats:styled-content>ctn1\u20102 (<jats:styled-content style=\"fixed-case\">S<\/jats:styled-content>lc22a4\u20105) are not involved. Melanin\/retinal toxic drugs like antimalarials (amodiaquine, quinine), quinidine and tricyclic antidepressants (imipramine) acted as inhibitors of this proton\u2010antiporter. The endogenous indole derivative tryptamine inhibited the transporter, unlike 5\u2010<jats:styled-content style=\"fixed-case\">HT<\/jats:styled-content>(serotonin), dopamine or L\u2010<jats:styled-content style=\"fixed-case\">DOPA<\/jats:styled-content>.<jats:italic>Trans<\/jats:italic>\u2010stimulation experiments with [<jats:sup>3<\/jats:sup><jats:styled-content style=\"fixed-case\">H<\/jats:styled-content>]\u2010clonidine at the<jats:styled-content style=\"fixed-case\">BRB<\/jats:styled-content>indicated that diphenhydramine, nicotine, oxycodone, naloxone, tramadol, 3,4\u2010methylenedioxyamphetamine (<jats:styled-content style=\"fixed-case\">MDMA<\/jats:styled-content>, ecstasy), heroin, methadone and verapamil are common substrates.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>A proton\u2010antiporter is physiologically involved in the transport of clonidine and diphenhydramine and is quantitatively more important than their passive diffusion flux at the mouse<jats:styled-content style=\"fixed-case\">BRB<\/jats:styled-content>. The features of this molecularly unidentified transporter highlight its importance in regulating drug delivery at the retina and suggest that it has the capacity to handle several drugs.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13246","type":"journal-article","created":{"date-parts":[[2015,7,14]],"date-time":"2015-07-14T16:43:52Z","timestamp":1436892232000},"page":"4714-4725","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":36,"title":["A polyspecific drug\/proton antiporter mediates diphenhydramine and clonidine transport at the mouse blood\u2010retinal barrier"],"prefix":"10.1111","volume":"172","author":[{"given":"H\u00e9l\u00e8ne","family":"Chapy","sequence":"first","affiliation":[{"name":"Variabilit\u00e9 de r\u00e9ponse aux psychotropes INSERM U1144 Paris France"},{"name":"UMR\u2010S 1144 Universit\u00e9 Paris Descartes Paris France"},{"name":"UMR\u2010S 1144 Universit\u00e9 Paris Diderot Paris 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