Received for publication August 27, 2007.
Revised November 20, 2007.
Accepted for publication November 20, 2007.

P-glycoprotein restricts the penetration of oseltamivir across the blood-brain barrier

Abstract

Oseltamivir is an ethyl ester prodrug of Ro 64-0802, the anti-influenza drug. Abnormal behavior has been suspected to be associated with oseltamivir medication in Japan. The purpose of the present study is to examine the involvement of transporters in the brain distribution of oseltamivir and its active form Ro 64-0802 across the blood-brain barrier. The brain-to-plasma concentration ratio (K_p,brain) of oseltamivir after intravenous infusion of oseltamivir in FVB mice was increased by pretreatment with GF120918, a dual inhibitor for P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), while that of Ro 64-0802 was only slightly increased. Furthermore, the distribution volume of Ro 64-0802 following intravenous administration of Ro 64-0802 in the brain was similar to the capillary volume, suggesting its minimal distribution. The K_p,brain value of oseltamivir in Mdr1a/1b P-gp knockout mice was 5.5-fold higher than that in wild-type mice, and comparable with that obtained by pretreatment with GF120918, while it was unchanged in Bcrp knockout mice. The K_p,brain value of oseltamivir was significantly higher in newborn rats, which is in good agreement with the ontogenetic expression profile of P-gp. Intracellular accumulation of oseltamivir was lower in human and mouse P-gp-expressing cells, which was reversed by P-gp inhibitor PSC833. These results suggest that P-gp limits the brain uptake of oseltamivir at the blood-brain barrier, and that Ro 64-0802 itself barely crosses the blood-brain barrier. However, it may be possible that Ro 64-0802 is formed in the brain from the oseltamivir, considering the presence of CES in the brain endothelial cells.

Key words: ABC transporters, blood-brain barrier, permeability, p-glycoprotein