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INTRODUCTIONOseltamivir is an ester-type prodrug of the neuraminidase inhibitor [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic acid (Ro 64-0802), which targets the A and B strains of influenza virus. This drug has been widely used in Japan and is stored on a large scale for use if an influenza pandemic occurs. However, there have been reports, though cases are rare, that infants and young patients taking oseltamivir have developed neuropsychiatric side effects, including mental instability and suicidal tendencies. Accordingly, The Ministry of Health, Labor and Welfare in Japan has restricted the use of this drug in teenagers and younger patients. The mechanisms of this putative side effect are not presently clear, though several studies have demonstrated that oseltamivir and Ro 64-0802 have an excitatory effect on hippocampal neurons (Izumi et al., 2007;Usami et al., 2008), a dopamine-releasing effect in the prefrontal cortex (Yoshino et al., 2008), and a hypothermia-promoting effect (Ono et al., 2008) in experimental animals.We have been studying the brain distribution of oseltamivir and Ro 64-0802 in animals (Morimoto et al., 2008). The distribution volume of Ro 64-0802 in the brain was equivalent to the vascular space. This suggested that the low lipophilicity of Ro 64-0802 (calculated clogP value of -0.97) restricts its penetration through the BBB by passive diffusion (Morimoto et al., 2008). On the other hand, the ester-type prodrug oseltamivir showed a more than ten-fold higher brain distribution compared with Ro 64-0802, reflecting its higher clogP value of 1.29. We have also demonstrated that the brain distribution of oseltamivir is limited by P-glycoprotein (P-gp)-mediated efflux transport at the blood-brain barrier: the brain concentration of oseltamivir in mdr1a/1b knockout mice was five-fold higher than that of wild-type mice (Morimoto et al., 2008 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 estim...