Penetration of oseltamivir and its active metabolite into the brain after lipopolysaccharide-induced inflammation in mice.
OBJECTIVE
Oseltamivir phosphate is used for the treatment of influenza virus infections. Recently, oral intake has been associated with abnormal behaviour. The present study examined the brain penetration of oseltamivir phosphate and oseltamivir carboxylate, its active metabolite, during inflammation.


METHODS
Male C57BL/6 mice were given three i.p. injections of lipopolysaccharide (LPS) or saline. We studied the concentration of Evans blue (a marker of blood-brain barrier function) and oseltamivir phosphate and its active metabolite in the brain and plasma.


RESULTS
The brain-to-plasma ratio of Evans blue compared with saline-treated control mice increased significantly with LPS dose. LPS-induced inflammation increased the permeation of drugs through the blood-brain barrier. The concentration of oseltamivir phosphate in both brain and plasma was 2-fold higher in mice treated with LPS than in control mice. Although the plasma concentration of the active carboxylate was not significantly altered by inflammation, the brain concentration was increased 2.7-fold in mice treated with LPS compared with control mice.


CONCLUSIONS
Administration of oseltamivir phosphate in the presence of inflammation increased the brain concentration of both parent drug and active metabolite, which may explain the central nervous system side-effects observed with this agent.
Oshima
Shigeru
S
Faculty of Pharmaceutical Sciences, Josai University, Sakado, Saitama, Japan.
Nemoto
Eiichi
E
Kuramochi
Mika
M
Saitoh
Yukiya
Y
Kobayashi
Daisuke
D
D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D005070:Evans Blue / Q000493:pharmacokinetics; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism*; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects*; D053139:Oseltamivir / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*
D000998:Antiviral Agents; D008070:Lipopolysaccharides; D053139:Oseltamivir; D005070:Evans Blue; C535162:oseltamivir carboxylate