title: Involvement of a proton-coupled organic cation antiporter in the blood-brain barrier transport of amantadine.
abstract: The blood-to-brain transport of amantadine, a weak N-methyl-d-aspartate (NMDA) antagonist, has been shown previously to participate in the cationic drug-sensitive transport system across the mouse blood-brain barrier (BBB). The purpose of the present study was to characterize the influx transport system by means of both an in situ mouse brain perfusion technique and in vitro studies using rat immortalized brain capillary endothelial cells (GPNT). The observed concentration-dependent initial uptake rate of [(3) H]amantadine suggested the involvement of a carrier-mediated transport mechanism. The normal uptake at physiological pH 7.4 was decreased by 72.9% in acidic perfusate, while it was increased by 35.3% in alkaline perfusate. These results suggest that pH-dependent transport is regulated by utilizing an oppositely directed proton gradient as a driving force. In addition, the [(3) H]amantadine uptake was moderately inhibited by the adamantane structural analogs (rimantadine and memantine) and other cationic drugs (pyrilamine, clonidine, nicotine, etc.), but not by substrates or inhibitors of the well-characterized organic cation transporters (tetraethylammonium, l-carnitine and choline). A similar inhibition pattern was observed between the in vivo studies and the in vitro experiments. These results indicate that the influx transport for amantadine across the BBB involves a proton-coupled organic cation antiporter. Copyright © 2016 John Wiley & Sons, Ltd.
authors.affiliation: Laboratory of Pharmaceutics, School of Pharamcy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan. suzuki.toyofumi@nihon-u.ac.jp.
authors.forename: Toyofumi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Laboratory of Clinical Pharmacokinetics, School of Pharamcy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Aoyama
authors.affiliation: Laboratory of Pharmaceutics, School of Pharamcy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Suzuki
authors.affiliation: Nihon Pharmaceutical University, Kita-adachi, Saitama, 362-0806, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Kobayashi
authors.affiliation: Department of Molecular Pharmaceutics, Meiji Pharmaceutical University, Kiyose, Tokyo, 204-8588, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fukami
authors.affiliation: Laboratory of Clinical Pharmacokinetics, School of Pharamcy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Matsumoto
authors.affiliation: Laboratory of Pharmaceutics, School of Pharamcy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba 274-8555, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tomono
mesh_terms: D000547:Amantadine / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D017920:Antiporters / Q000378:metabolism*; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D051381:Rats
chemical_list: D017920:Antiporters; D000547:Amantadine
keywords: amantadine; blood-brain barrier; mouse brain perfusion; proton-coupled organic cation antiporter; rat immortalized brain capillary endothelial cells