title: Developmental changes of brain distribution and localization of oseltamivir and its active metabolite Ro 64-0802 in rats.
abstract: Oseltamivir, a prodrug of the neuraminidase inhibitor [3R, 4R, 5S]-4-Acetamide-5-amino-3-(1-ethylpropyl)-1-cyclohexene-1-carboxylate phosphate (Ro 64-0802), is widely used for treatment of influenza infections in Japan, but may be associated with mental instability and suicidal tendencies as a rare side effect, especially in infants and young patients. We examined developmental changes in the brain distribution of oseltamivir and Ro 64-0802, and in the expression of P-glycoprotein (P-gp) at the blood-brain barrier (BBB) in rats by 8 weeks. Brain concentration and Kp(,app,brain) (brain-to-plasma concentration ratio) of oseltamivir were highest in 2-week-old rats (1.45 µg/g brain and 0.14, respectively), and were negatively correlated with both age and P-gp expression at the BBB. In contrast, brain concentration and Kp(,app,brain) of Ro 64-0802 after oral gavage of oseltamivir were lowest in 2-week-old rats (0.02 µg/g brain and 0.02), and increased with age. Mass imaging analysis revealed that both compounds were distributed homogenously in brain cross-sections, including the hippocampus. From these results, it was estimated that oseltamivir concentration throughout the brain cross-sections was 70-fold and 0.9-fold higher than that of Ro 64-0802 in 2-week-old and 8-week-old rats, respectively. Such developmental changes of prodrug/drug concentration ratio, if they also occur in humans, may provide a rational basis for the putative central nervous system (CNS) side effects in young patients.
authors.affiliation: Takasaki University of Health and Welfare, Gunma, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Morimoto
authors.forename: Takaaki
authors.initials: T
authors.lastname: Nagami
authors.forename: Noriko
authors.initials: N
authors.lastname: Matsumoto
authors.forename: Sho
authors.initials: S
authors.lastname: Wada
authors.forename: Takashi
authors.initials: T
authors.lastname: Kano
authors.forename: Chihaya
authors.initials: C
authors.lastname: Kakinuma
authors.forename: Takuo
authors.initials: T
authors.lastname: Ogihara
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000081:Acetamides / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D000818:Animals; D000998:Antiviral Agents / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000254:growth & development* / Q000378:metabolism*; D008297:Male; D053139:Oseltamivir / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000081:Acetamides; D000998:Antiviral Agents; C403132:Ro 64-0802; D053139:Oseltamivir