Developmental changes of brain distribution and localization of oseltamivir and its active metabolite Ro 64-0802 in rats

• Morimoto Kaori

  Faculty of Pharmacy, Takasaki University of Health and Welfare

• Nagami Takaaki

  Faculty of Pharmacy, Takasaki University of Health and Welfare

• Matsumoto Noriko

  Faculty of Pharmacy, Takasaki University of Health and Welfare

• Wada Sho

  Faculty of Pharmacy, Takasaki University of Health and Welfare

• Kano Takashi

  Faculty of Pharmacy, Takasaki University of Health and Welfare

• Kakinuma Chihaya

  Faculty of Pharmacy, Takasaki University of Health and Welfare

• Ogihara Takuo

  Faculty of Pharmacy, Takasaki University of Health and Welfare

抄録

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.

収録刊行物

• Ｔｈｅ　Ｊｏｕｒｎａｌ　ｏｆ　Ｔｏｘｉｃｏｌｏｇｉｃａｌ　Ｓｃｉｅｎｃｅｓ

  Ｔｈｅ　Ｊｏｕｒｎａｌ　ｏｆ　Ｔｏｘｉｃｏｌｏｇｉｃａｌ　Ｓｃｉｅｎｃｅｓ 37 (6), 1217-1223, 2012

  一般社団法人　日本毒性学会

キーワード

• Brain
• Distribution
• Age
• Oseltamivir
• Rat

詳細情報

• CRID: 1390282679883034112
• NII論文ID: 130004447021
• NII論文ID: 10031126025
• NII書誌ID: AN00002808
• DOI: 10.2131/jts.37.1217
• COI: 1:CAS:528:DC%2BC3sXhsVans7o%3D
• ISSN: 18803989
• ISSN: 03881350
• NDL書誌ID: 024151624
• PubMed: 23208436
• Web Site: http://id.ndl.go.jp/bib/024151624
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I024151624
• Web Site: https://www.jstage.jst.go.jp/article/jts/37/6/37_1217/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2013248580
• 本文言語コード: en
• データソース種別:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
  • KAKEN
• 抄録ライセンスフラグ: 使用不可