論文 - 詳細
| RRC ID | 43141 |
|---|---|
| 著者 | Morimoto K, Nakakariya M, Shirasaka Y, Kakinuma C, Fujita T, Tamai I, Ogihara T. |
| タイトル | Oseltamivir (Tamiflu) efflux transport at the blood-brain barrier via P-glycoprotein. |
| ジャーナル | Drug Metab Dispos |
| Abstract |
Oseltamivir (Tamiflu, Roche, Nutley, NJ), an ester-type prodrug of the anti-influenza drug Ro 64-0802 (oseltamivir carboxylate), has been reported to be associated with neuropsychiatric side effects, which are likely to be caused by distribution of oseltamivir and/or its metabolite into the central nervous system. Enhanced toxicity and brain distribution of oseltamivir in unweaned rats led us to hypothesize that the low level of distribution of oseltamivir and/or Ro 64-0802 in adult brain was caused by the presence of a specific efflux transporter at the blood-brain barrier. We examined the possible role of P-glycoprotein (P-gp) as the determinant of brain distribution of oseltamivir and Ro 64-0802 both in vitro using LLC-GA5-COL150 cells, which overexpress human multidrug resistance protein 1 P-gp on the apical membrane, and in vivo using mdr1a/1b knockout mice. The permeability of oseltamivir in the basal-to-apical direction was significantly greater than that in the opposite direction. The directional transport disappeared on addition of cyclosporin A, a P-gp inhibitor. The brain distribution of oseltamivir was increased in mdr1a/1b knockout mice compared with wild-type mice. In contrast, negligible transport of Ro 64-0802 by P-gp was observed in both in vitro and in vivo studies. These results show that oseltamivir, but not Ro 64-0802, is a substrate of P-gp. Accordingly, low levels of P-gp activity or drug-drug interactions at P-gp may lead to enhanced brain accumulation of oseltamivir, and this may in turn account for the central nervous system effects of oseltamivir observed in some patients. |
| 巻・号 | 36(1) |
| ページ | 6-9 |
| 公開日 | 2008-1-1 |
| DOI | 10.1124/dmd.107.017699 |
| PII | dmd.107.017699 |
| PMID | 17940134 |
| MeSH | ATP Binding Cassette Transporter, Subfamily B / genetics ATP Binding Cassette Transporter, Subfamily B / metabolism* ATP-Binding Cassette Transporters / genetics ATP-Binding Cassette Transporters / metabolism* Animals Antiviral Agents / blood Antiviral Agents / pharmacokinetics* Blood-Brain Barrier / metabolism* Cell Line Cell Membrane Permeability Cloning, Molecular Humans Male Mice Mice, Knockout Oseltamivir / blood Oseltamivir / pharmacokinetics* Tissue Distribution |
| IF | 3.231 |
| 引用数 | 82 |
| WOS 分野 | PHARMACOLOGY & PHARMACY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | Patent(IFI CLAIMS) |
| 各媒体での言及数の合計 | 2 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | LLC-GA5-CoL150(RCB0871) |