論文 - 詳細
| RRC ID | 41660 |
|---|---|
| 著者 | Yamamoto C, Murakami H, Koyabu N, Takanaga H, Matsuo H, Uchiumi T, Kuwano M, Naito M, Tsuruo T, Ohtani H, Sawada Y. |
| タイトル | Contribution of P-glycoprotein to efflux of ramosetron, a 5-HT3 receptor antagonist, across the blood-brain barrier. |
| ジャーナル | J Pharm Pharmacol |
| Abstract |
In-situ rat and mouse brain perfusion data indicated that the brain distribution of ramosetron (R-ramosetron), a 5-hydroxytryptamine3 (5-HT3) receptor antagonist, was extremely low compared with that expected from its lipophilicity. We hypothesized the involvement of an efflux system(s) and investigated the contribution of P-glycoprotein to efflux transport of ramosetron across the blood-brain barrier by means of an in-vitro uptake study in cell lines that over-express P-glycoprotein. We examined the contributions of mdr1a, mdr1b and MDR1 P-glycoprotein by using LV500 cells, MBEC4 cells and LLC-GA5-COL300 cells, which over-express mdr1a P-glycoprotein, mdr1b P-glycoprotein and MDR1 P-glycoprotein, respectively. The uptake of [14C]ramosetron by LV500 cells and LLC-GA5-COL300 cells was significantly lower than that by the respective parental cells. Next, we studied the effects of P-glycoprotein inhibitors, verapamil and ciclosporin, on uptake of [14C]ramosetron by these cell lines. The uptake of [14C]ramosetron by LV500 cells and LLC-GA5-COL300 cells was significantly increased in the presence of verapamil or ciclosporin, while verapamil did not affect the uptake of [14C]ramosetron by MBEC4 cells. These results indicate that the efflux of [14C]ramosetron is partly mediated by mdr1a P-glycoprotein, but not by mdr1b P-glycoprotein, and that there is a difference in substrate specificity between mdr1a P-glycoprotein and mdr1b P-glycoprotein. Further, [14C]ramosetron was confirmed to be effluxed by human MDR1 P-glycoprotein. We conclude that the limited distribution of ramosetron to the brain is due, at least in part, to efflux mediated by the P-glycoprotein at the blood-brain barrier. |
| 巻・号 | 54(8) |
| ページ | 1055-63 |
| 公開日 | 2002-8-1 |
| DOI | 10.1211/002235702320266208 |
| PMID | 12195819 |
| MeSH | ATP Binding Cassette Transporter, Subfamily B / pharmacology* ATP Binding Cassette Transporter, Subfamily B, Member 1 / pharmacology* ATP-Binding Cassette Transporters / pharmacology* Animals Benzimidazoles / pharmacokinetics* Blood-Brain Barrier* Carbon Radioisotopes Cell Line Drug Resistance, Multiple Male Mice Rats Rats, Wistar Serotonin Antagonists / pharmacokinetics* |
| IF | 2.571 |
| 引用数 | 25 |
| 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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| 各媒体での言及数の合計 | 0 |
| リソース情報 | |
| ヒト・動物細胞 | LLC-GA5-COL300(RCB0872) |