P-glycoprotein Restricts the Penetration of Oseltamivir Across the Blood-Brain Barrier

Abstract

ABSTRACT: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.Oseltamivir (Fig. 1) is an ester prodrug of Ro 64-0802, a potent and selective inhibitor of neuraminidase, resulting in an inhibition of release of influenza virus from the host cells and growth of influenza virus. Oseltamivir is used in the treatment and prophylaxis of both Influenzavirus A and Influenzavirus B (Bardsley-Elliot and Noble, 1999). The number of prescribed oseltamivir has reached approximately 10 million in Japan, which accounted for 75% of the world total in 2006. Recently, abnormal behavior has been reported in influenza patients prescribed oseltamivir (http://www.fda.gov/cder/ drug/infopage/tamiflu/QA20051117.htm; Fuyuno, 2007). According to a report by the Ministry of Health, Labor, and Welfare, the number of people who behaved abnormally following oseltamivir treatment has increased to 211 (0.002% of all patients), approximately 80% of whom are teenagers or younger. The relationship between abnormal behavior and oseltamivir medication remains an open question and has not yet been elucidated. The Ministry of Health, Labor, and Welfare has published a caution for oseltamivir medication to teenagers or younger...

Cerebrospinal Fluid Can Be Used as a Surrogate to Assess Brain Exposures of Breast Cancer Resistance Protein and P-Glycoprotein Substrates

“…Various studies have demonstrated that the penetration of a vast variety of drugs across the blood-brain barrier (BBB) is determined by Pgp (Schinkel et al, 1997;Chen et al, 2003;Ose et al, 2008). Similar to Pgp, the expression of Bcrp on the luminal membrane of brain endothelial cells has been demonstrated (Daood et al, 2008;Roberts et al, 2008).…”

Species-Dependent Uptake of Glycylsarcosine but Not Oseltamivir in Pichia pastoris Expressing the Rat, Mouse, and Human Intestinal Peptide Transporter PEPT1

“…More recently, however, there have been postmarketing reports (mostly from Japan) of neuropsychiatric side effects in younger patients taking oseltamivir, in some cases resulting in fatal outcomes (http://www.gene.com/gene/products/information/tamiflu/pdf/pi.pdf). This finding has led to a number of studies evaluating the mechanism by which oseltamivir and oseltamivir carboxylate are transported across capillary endothelial cells forming the blood-brain barrier (Morimoto et al, 2008;Ose et al, 2008Ose et al, , 2009. It was demonstrated that oseltamivir and its active metabolite were actively effluxed by luminally expressed P-glycoprotein (Pgp) and multidrug resistance-associated protein 4, respectively, thereby limiting their penetration in brain.…”

Oseltamivir Enhances Hippocampal Network Synchronization

“…Animal experiments with rodents demonstrate that orally (30 -300 mg/ kg) or intravenously (8 µmol / h per kg) administered oseltamivir accumulates in the brain via the blood-brain barrier, the brain-to-plasma concentration ratio ranging from 0.1 -0.7 (roughly equal to 0.1 -5 µM in the brain) (13,14). Safety examinations of Tamiflu TM (oseltamivir), conducted by Roche, show that in 7 -14-day-old rats, the brain concentration reaches more than 500 times greater than that in adult animals (see basic product information of Tamiflu TM ), suggesting a higher risk of a side-effect in younger brains.…”