Evaluation of [11C]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

Chie Seki, Arata Oh-Nishi, Yuji Nagai, Takafumi Minamimoto, Shigeru Obayashi, Makoto Higuchi, Makoto Takei, Kenji Furutsuka, Takehito Ito, Ming Rong Zhang, Hiroshi Ito, Mototsugu Ito, Sumito Ito, Hiroyuki Kusuhara, Yuichi Sugiyama, Tetsuya Suhara

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

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 [11C]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 [11C]oseltamivir PET scan and serial arterial blood sampling were performed to obtain [11C]oseltamivir kinetics. Brain uptake of [11C]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 [11C]oseltamivir were 0.0033 and 0.0035% ID/cm3 × 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/cm3 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 [11C]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.

Original languageEnglish
Article number24
Pages (from-to)1-10
Number of pages10
JournalEJNMMI Research
Volume4
Issue number1
DOIs
Publication statusPublished - 01-12-2014
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Radiology Nuclear Medicine and imaging

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