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 (Kp,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 Kp,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 Kp,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.
Footnotes
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This study was supported by Grants-in-Aid for Scientific Research (A) from the Japan Society for the Promotion of Science (JSPS) (KAKENHI 17209005).
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.107.018556.
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ABBREVIATIONS: Ro 64-0802, [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate; BBB, blood-brain barrier; hCES1, human carboxylesterase 1; OAT, organic anion transporter; P-gp, P-glycoprotein; Bcrp, breast cancer resistance protein; GF120918, 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; MDR, multidrug-resistant; PSC833, valspodar; mMdr1a-LLC-PK1, mouse Mdr1a-expressed LLC-PK1; MDCKII, Madin-Darby canine kidney II; hMDR1-MDCKII, human MDR1-expressed MDCKII; gapdh, glyceraldehyde-3-phosphate dehydrogenase; PCR, polymerase chain reaction; PBS, phosphate-buffered saline; TBST, Tris-buffered saline/Tween 20; ECL, enhanced chemiluminescence; LC/MS, liquid chromatography/mass spectrometry; Kp,brain, brain-to-plasma concentration ratio; CES, carboxylesterase; SNP, single nucleotide polymorphism.
- Received August 27, 2007.
- Accepted November 20, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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