title: Evaluation of [(11)C]oseltamivir uptake into the brain during immune activation by systemic polyinosine-polycytidylic acid injection: a quantitative PET study using juvenile monkey models of viral infection.
abstract: BACKGROUND
  Abnormal behaviors of young patients after taking the anti-influenza agent oseltamivir (Tamiflu®, F. Hoffmann-La Roche, Ltd., Basel, Switzerland) have been suspected as neuropsychiatric adverse events (NPAEs). Immune response to viral infection is suspected to cause elevation of drug concentration in the brain of adolescents. In the present study, the effect of innate immune activation on the brain uptake of [(11)C]oseltamivir was quantitatively evaluated in juvenile monkeys.
  
  
  METHODS
  Three 2-year-old monkeys underwent positron emission tomography (PET) scans at baseline and immune-activated conditions. Both scans were conducted under pre-dosing of clinically relevant oseltamivir. The immune activation condition was induced by the intravenous administration of polyinosine-polycytidylic acid (poly I:C). Dynamic [(11)C]oseltamivir PET scan and serial arterial blood sampling were performed to obtain [(11)C]oseltamivir kinetics. Brain uptake of [(11)C]oseltamivr was evaluated by its normalized brain concentration, brain-to-plasma concentration ratio, and plasma-to-brain transfer rate. Plasma pro-inflammatory cytokine levels were also measured.
  
  
  RESULTS
  Plasma interleukin-6 was elevated after intravenous administration of poly I:C in all monkeys. Brain radioactivity was uniform both at baseline and under poly I:C treatment. The mean brain concentrations of [(11)C]oseltamivir were 0.0033 and 0.0035% ID/cm(3) × kg, the mean brain-to-plasma concentration ratios were 0.58 and 0.65, and the plasma-to-brain transfer rates were 0.0047 and 0.0051 mL/min/cm(3) for baseline and poly I:C treatment, respectively. Although these parameters were slightly changed by immune activation, the change was not notable.
  
  
  CONCLUSIONS
  The brain uptake of [(11)C]oseltamivir was unchanged by poly I:C treatment in juvenile monkeys. This study demonstrated that the innate immune response similar to the immune activation of influenza would not notably change the brain concentration of oseltamivir in juvenile monkeys.
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku 265-8555, Chiba, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Seki
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku 265-8555, Chiba, Japan.
authors.forename: Arata
authors.initials: A
authors.lastname: Oh-Nishi
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku 265-8555, Chiba, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nagai
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku 265-8555, Chiba, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Minamimoto
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku 265-8555, Chiba, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Obayashi
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku 265-8555, Chiba, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku 265-8555, Chiba, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Takei
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku 265-8555, Chiba, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Furutsuka
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku 265-8555, Chiba, Japan.
authors.forename: Takehito
authors.initials: T
authors.lastname: Ito
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku 265-8555, Chiba, Japan.
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku 265-8555, Chiba, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ito
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku 133-0033, Tokyo, Japan.
authors.forename: Mototsugu
authors.initials: M
authors.lastname: Ito
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku 133-0033, Tokyo, Japan.
authors.forename: Sumito
authors.initials: S
authors.lastname: Ito
authors.affiliation: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku 133-0033, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kusuhara
authors.affiliation: Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, 1-6, Suehiro-cho, Tsurumi-ku, Yokohama 230-0045, Kanagawa, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
authors.affiliation: Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku 265-8555, Chiba, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
keywords: Brain; Monkey; Oseltamivir; Poly I:C; Positron emission tomography