title: A polyspecific drug/proton antiporter mediates diphenhydramine and clonidine transport at the mouse blood-retinal barrier.
abstract: OBJECTIVE
  Transporters at the blood-retinal barrier (BRB), as at the blood-brain barrier (BBB), regulate the distribution of compounds into the neural parenchyma. However, the expression of BRB transporters and their quantitative impact in vivo are still poorly understood.
  
  
  METHODS
  Clonidine and diphenhydramine are substrates of a novel BBB drug/proton-antiporter. We evaluated their transport at the BRB by in situ carotid perfusion in wild-type or knocked-out mice for Oct1-3 (Slc22a1-3).
  
  
  RESULTS
  At pharmacological exposure levels, carrier-mediated BRB 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-capacity potassium- and sodium-independent proton-antiporter that shared the features of the previously characterized clonidine, diphenhydramine and cocaine BBB transporter. The functional characterization suggests that SLC transporters Oct1-3, Mate1 (Slc47a1) and Octn1-2 (Slc22a4-5) are not involved. Melanin/retinal toxic drugs like antimalarials (amodiaquine, quinine), quinidine and tricyclic antidepressants (imipramine) acted as inhibitors of this proton-antiporter. The endogenous indole derivative tryptamine inhibited the transporter, unlike 5-HT (serotonin), dopamine or L-DOPA. Trans-stimulation experiments with [(3) H]-clonidine at the BRB indicated that diphenhydramine, nicotine, oxycodone, naloxone, tramadol, 3,4-methylenedioxyamphetamine (MDMA, ecstasy), heroin, methadone and verapamil are common substrates.
  
  
  CONCLUSIONS
  A proton-antiporter is physiologically involved in the transport of clonidine and diphenhydramine and is quantitatively more important than their passive diffusion flux at the mouse BRB. 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.
authors.affiliation: Variabilité de réponse aux psychotropes, INSERM U1144, Paris, France.|UMR-S 1144, Université Paris Descartes, Paris, France.|UMR-S 1144, Université Paris Diderot, Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Chapy
authors.affiliation: Variabilité de réponse aux psychotropes, INSERM U1144, Paris, France.|UMR-S 1144, Université Paris Descartes, Paris, France.|UMR-S 1144, Université Paris Diderot, Paris, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: André
authors.affiliation: Variabilité de réponse aux psychotropes, INSERM U1144, Paris, France.|UMR-S 1144, Université Paris Descartes, Paris, France.|UMR-S 1144, Université Paris Diderot, Paris, France.|Pharmacokinetics, Assistance Publique des Hôpitaux de Paris - AP-HP, Paris, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Declèves
authors.affiliation: Variabilité de réponse aux psychotropes, INSERM U1144, Paris, France.|UMR-S 1144, Université Paris Descartes, Paris, France.|UMR-S 1144, Université Paris Diderot, Paris, France.|Pharmacokinetics, Assistance Publique des Hôpitaux de Paris - AP-HP, Paris, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Scherrmann
authors.affiliation: Variabilité de réponse aux psychotropes, INSERM U1144, Paris, France.|UMR-S 1144, Université Paris Descartes, Paris, France.|UMR-S 1144, Université Paris Diderot, Paris, France.|Pharmacokinetics, Assistance Publique des Hôpitaux de Paris - AP-HP, Paris, France.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cisternino
mesh_terms: D000818:Animals; D017920:Antiporters / Q000378:metabolism*; D001692:Biological Transport; D001813:Blood-Retinal Barrier / Q000378:metabolism*; D003000:Clonidine / Q000494:pharmacology*; D004155:Diphenhydramine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout
chemical_list: D017920:Antiporters; D004155:Diphenhydramine; D003000:Clonidine