title: Oseltamivir (Tamiflu) efflux transport at the blood-brain barrier via P-glycoprotein.
abstract: Oseltamivir (Tamiflu, Roche, Nutley, NJ), an ester-type prodrug of the anti-influenza drug Ro 64-0802 (oseltamivir carboxylate), has been reported to be associated with neuropsychiatric side effects, which are likely to be caused by distribution of oseltamivir and/or its metabolite into the central nervous system. Enhanced toxicity and brain distribution of oseltamivir in unweaned rats led us to hypothesize that the low level of distribution of oseltamivir and/or Ro 64-0802 in adult brain was caused by the presence of a specific efflux transporter at the blood-brain barrier. We examined the possible role of P-glycoprotein (P-gp) as the determinant of brain distribution of oseltamivir and Ro 64-0802 both in vitro using LLC-GA5-COL150 cells, which overexpress human multidrug resistance protein 1 P-gp on the apical membrane, and in vivo using mdr1a/1b knockout mice. The permeability of oseltamivir in the basal-to-apical direction was significantly greater than that in the opposite direction. The directional transport disappeared on addition of cyclosporin A, a P-gp inhibitor. The brain distribution of oseltamivir was increased in mdr1a/1b knockout mice compared with wild-type mice. In contrast, negligible transport of Ro 64-0802 by P-gp was observed in both in vitro and in vivo studies. These results show that oseltamivir, but not Ro 64-0802, is a substrate of P-gp. Accordingly, low levels of P-gp activity or drug-drug interactions at P-gp may lead to enhanced brain accumulation of oseltamivir, and this may in turn account for the central nervous system effects of oseltamivir observed in some patients.
authors.affiliation: Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki, Gunma, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Morimoto
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakakariya
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Shirasaka
authors.forename: Chihaya
authors.initials: C
authors.lastname: Kakinuma
authors.forename: Takuya
authors.initials: T
authors.lastname: Fujita
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
authors.forename: Takuo
authors.initials: T
authors.lastname: Ogihara
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000998:Antiviral Agents / Q000097:blood / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002460:Cell Line; D002463:Cell Membrane Permeability; D003001:Cloning, Molecular; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053139:Oseltamivir / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D000998:Antiviral Agents; D053139:Oseltamivir; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3