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

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.

Effect of milk on the pharmacokinetics of oseltamivir in healthy volunteers.

We previously showed that oseltamivir, a prodrug of the influenza virus neuraminidase inhibitor Ro 64-0802, is a substrate of proton-coupled oligopeptide transporter (PEPT1), and its intestinal absorption in rats is markedly inhibited by administration with milk. To investigate the importance of PEPT1 for oseltamivir absorption in humans, and the characteristics of the drug-milk interaction, a crossover clinical study was conducted in healthy volunteers, who received 75 mg of oseltamivir with 400 mL of water or milk. Milk significantly reduced the maximum plasma concentration (C(max) ) and the area under the plasma concentration-time curve from 0 to 2 h (AUC(0-2) ) of both oseltamivir and Ro 64-0802 (oseltamivir, 68.9% and 34.5%; Ro 64-0802, 69.5% and 14.2%, respectively, vs. water), but had no significant effect on the apparent terminal half-life (t(1/2) ) or AUC(0-∞) . Urinary recovery of oseltamivir and Ro 64-0802 was significantly reduced to 77.5% of the control by milk. The early reduction of oseltamivir absorption might be through the PEPT1 inhibition by milk peptides. However, the extent of interaction in humans was limited as compared with that in rats, possibly because of species difference in the PEPT1 expression and its contribution. This might be the first report suggesting the clinical drug-food interaction via PEPT1.