Oseltamivir is an ethyl
ester prodrug of [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-
cyclohexene-1-carboxylate
phosphate (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 (BBB). The brain-to-plasma concentration ratio (K(p,brain)) of
oseltamivir after i.v. infusion of
oseltamivir in FVB mice was increased by pretreatment with N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-
acridine carboxamide (
GF120918), a dual inhibitor for
P-glycoprotein (P-gp) and
breast cancer resistance
protein (Bcrp), whereas that of
Ro 64-0802 was only slightly increased. Furthermore, the distribution volume of
Ro 64-0802 following i.v. 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 multidrug-resistant (Mdr) 1a/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, whereas 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
valspodar (
PSC833). These results suggest that P-gp limits the brain uptake of
oseltamivir at the BBB and that
Ro 64-0802 itself barely crosses the BBB. However, it may be possible that
Ro 64-0802 is formed in the brain from the
oseltamivir, considering the presence of
carboxylesterase in the brain endothelial cells.