{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T05:59:39Z","timestamp":1790488779850,"version":"4.1.0"},"reference-count":47,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2014,12,21]],"date-time":"2014-12-21T00:00:00Z","timestamp":1419120000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biopharm &amp; Drug Disp"],"published-print":{"date-parts":[[2015,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>The purpose of this study was to characterize the brain\u2010to\u2010blood efflux transport of amantadine across the blood\u2013brain barrier (BBB). The apparent<jats:italic>in vivo<\/jats:italic>efflux rate constant for [<jats:sup>3<\/jats:sup>H]amantadine from the rat brain (<jats:italic>k<\/jats:italic><jats:sub>eff<\/jats:sub>) was found to be 1.53\u2009\u00d7\u200910<jats:sup>\u20102<\/jats:sup>\u2009min<jats:sup>\u20101<\/jats:sup>after intracerebral microinjection using the brain efflux index method. The efflux of [<jats:sup>3<\/jats:sup>H]amantadine was inhibited by 1\u2010methyl\u20104\u2010phenylpyridinium (MPP<jats:sup>+<\/jats:sup>), a cationic neurotoxin, suggesting that amantadine transport from the brain to the blood across the BBB potentially involves the rat plasma membrane monoamine transporter (rPMAT). On the other hand, other selected substrates for organic cation transporters (OCTs) and organic anion transporters (OATs), as well as inhibitors of P\u2010glycoprotein (P\u2010gp), did not affect the efflux transport of [<jats:sup>3<\/jats:sup>H]amantadine. In addition,<jats:italic>in vitro<\/jats:italic>studies using an immortalized rat brain endothelial cell line (GPNT) showed that the uptake and retention of [<jats:sup>3<\/jats:sup>H]amantadine by the cells was not changed by the addition of cyclosporin, which is an inhibitor of P\u2010gp. However, cyclosporin affected the uptake and retention of rhodamine123. Finally, the initial brain uptake of [<jats:sup>3<\/jats:sup>H]amantadine was determined using an<jats:italic>in situ<\/jats:italic>mouse brain perfusion technique. Notably, the brain uptake clearance for [<jats:sup>3<\/jats:sup>H]amantadine was significantly decreased with the co\u2010perfusion of quinidine or verapamil, which are cationic P\u2010gp inhibitors, while MPP<jats:sup>+<\/jats:sup>did not have a significant effect. It is thus concluded that while P\u2010gp is not involved, it is possible that rPMAT and the cationic drug\u2010sensitive transport system participate in the brain\u2010to\u2010blood efflux and the blood\u2010to\u2010brain influx of amantadine across the BBB, respectively. Copyright \u00a9 2014 John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/bdd.1926","type":"journal-article","created":{"date-parts":[[2014,11,20]],"date-time":"2014-11-20T11:23:24Z","timestamp":1416482604000},"page":"126-137","source":"Crossref","is-referenced-by-count":8,"title":["Possible involvement of cationic\u2010drug sensitive transport systems in the blood\u2010to\u2010brain influx and brain\u2010to\u2010blood efflux of amantadine across the blood\u2013brain barrier"],"prefix":"10.1002","volume":"36","author":[{"given":"Toyofumi","family":"Suzuki","sequence":"first","affiliation":[{"name":"Laboratory of Pharmaceutics, School of Pharmacy Nihon University 7\u20107\u20101 Narashinodai Funabashi Chiba 274\u20108555 Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiro","family":"Fukami","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmaceutics, School of Pharmacy Nihon University 7\u20107\u20101 Narashinodai Funabashi Chiba 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