title: P-glycoprotein limits the brain penetration of olopatadine hydrochloride, H1-receptor antagonist.
abstract: Olopatadine, a new second-generation antihistamine, is widely used in the treatment of allergic disorders. The low levels of histamine H1 receptor occupancy in human brain by olopatadine, which is related to its minimal sedation, suggest its low penetration into the brain. The present study evaluates the impact of P-glycoprotein (P-gp) on brain penetration and plasma concentration of olopatadine. The uptake amount of olopatadine in human P-gp transfected LLC-PK1 cells (LLC-GA5-COL150) was lower than that in LLC-PK1. The uptake of olopatadine in LLC-GA5-COL150 was increased in the same level as that in LLC-PK1 in the presence of cyclosporine A, a P-gp inhibitor. After intravenous or oral administration of olopatadine to wild type (WT) and mdr1a/1b knockout (KO) mice at a dose of 1 mg/kg, the brain concentration in KO mice was higher than that in WT mice. On the other hand, the plasma concentration of olopatadine after either route of administration was not different between WT and KO mice. These results suggest that olopatadine is a substrate of P-gp, and that P-gp limits the brain penetration but dose not affect the plasma concentration of olopatadine.
authors.affiliation: Pharmacokinetic Research Laboratories, Pharmaceutical Research Center, Kyowa Hakko Kogyo Co., Ltd., Sunto-gun, Shizuoka, Japan. nobuhito.mimura@kyowa.co.jp
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Mimura
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Nagata
authors.forename: Takashi
authors.initials: T
authors.lastname: Kuwabara
authors.forename: Nobuo
authors.initials: N
authors.lastname: Kubo
authors.forename: Eiichi
authors.initials: E
authors.lastname: Fuse
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D019540:Area Under Curve; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D003990:Dibenzoxepins / Q000493:pharmacokinetics*; D006634:Histamine H1 Antagonists / Q000493:pharmacokinetics*; D018374:LLC-PK1 Cells; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D000069605:Olopatadine Hydrochloride
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003990:Dibenzoxepins; D006634:Histamine H1 Antagonists; D000069605:Olopatadine Hydrochloride