title: Nasal delivery of P-gp substrates to the brain through the nose-brain pathway.
abstract: The objective of this study was to evaluate in rats the potential utility of the nasal route to enhance central nervous system (CNS) delivery of drugs recognized by P-glycoprotein (P-gp). Well-known P-gp substrates verapamil and talinolol were perfused nasally or infused intravenously, and when plasma concentrations following intravenous infusion and nasal perfusion showed similar profiles. The concentration of verapamil in the brain after nasal perfusion was twice that after intravenous infusion. Although talinolol in the brain and the cerebrospinal fluid after i.v. infusion were below the detection limit, it was detected after nasal perfusion. When rats were treated with cyclosporin A, brain concentrations of verapamil after both administration modes were increased significantly, while those of talinolol were not significantly changed. Since the permeability of talinolol is low, talinolol in the brain which was transported directly from the nasal cavity has little chance of transport by P-gp localized in the apical membrane of cerebral microvessel endothelial cells. The potential for drug delivery utilizing the nose-CNS route was confirmed for P-gp substrates. The advantage of nasal delivery over i.v. delivery of talinolol to the brain was more significant than that of verapamil, suggesting that nasal administration is more useful strategy for the brain delivery of low-permeability P-gp substrates than the use of P-gp inhibitors.
authors.affiliation: ADME Research Inc., Minoh, Japan. t.shingaki@adme.jp
authors.forename: Tomotaka
authors.initials: T
authors.lastname: Shingaki
authors.forename: Ismael J
authors.initials: IJ
authors.lastname: Hidalgo
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Furubayashi
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Sakane
authors.forename: Hidemasa
authors.initials: H
authors.lastname: Katsumi
authors.forename: Akira
authors.initials: A
authors.lastname: Yamamoto
authors.forename: Shinji
authors.initials: S
authors.lastname: Yamashita
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000281:Administration, Intranasal / Q000379:methods*; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D007262:Infusions, Intravenous; D008297:Male; D010477:Perfusion; D011412:Propanolamines / Q000008:administration & dosage* / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014700:Verapamil / Q000008:administration & dosage* / Q000097:blood / Q000134:cerebrospinal fluid / Q000378:metabolism / Q000493:pharmacokinetics*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; C011550:talinolol; D016572:Cyclosporine; D014700:Verapamil