Contribution of P-glycoprotein to efflux of ramosetron, a 5-HT3 receptor antagonist, across the blood-brain barrier

C. Yamamoto, H. Murakami, N. Koyabu, H. Takanaga, H. Matsuo, T. Uchiumi, M. Kuwano, M. Naito, T. Tsuruo, H. Ohtani, Y. Sawada

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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 contribution of mdr1a, mdr1b and MDR1 P-glycoprotein by using LV500 cells, MBEC4 cells and LL-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.

Original languageEnglish
Pages (from-to)1055-1063
Number of pages9
JournalJournal of Pharmacy and Pharmacology
Volume54
Issue number8
DOIs
Publication statusPublished - Aug 29 2002

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P-Glycoprotein
Blood-Brain Barrier
Verapamil
ramosetron
Cyclosporine
Brain
Cell Line
Substrate Specificity
Perfusion

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

Cite this

Contribution of P-glycoprotein to efflux of ramosetron, a 5-HT3 receptor antagonist, across the blood-brain barrier. / Yamamoto, C.; Murakami, H.; Koyabu, N.; Takanaga, H.; Matsuo, H.; Uchiumi, T.; Kuwano, M.; Naito, M.; Tsuruo, T.; Ohtani, H.; Sawada, Y.

In: Journal of Pharmacy and Pharmacology, Vol. 54, No. 8, 29.08.2002, p. 1055-1063.

Research output: Contribution to journalArticle

Yamamoto, C, Murakami, H, Koyabu, N, Takanaga, H, Matsuo, H, Uchiumi, T, Kuwano, M, Naito, M, Tsuruo, T, Ohtani, H & Sawada, Y 2002, 'Contribution of P-glycoprotein to efflux of ramosetron, a 5-HT3 receptor antagonist, across the blood-brain barrier', Journal of Pharmacy and Pharmacology, vol. 54, no. 8, pp. 1055-1063. https://doi.org/10.1211/002235702320266208
Yamamoto, C. ; Murakami, H. ; Koyabu, N. ; Takanaga, H. ; Matsuo, H. ; Uchiumi, T. ; Kuwano, M. ; Naito, M. ; Tsuruo, T. ; Ohtani, H. ; Sawada, Y. / Contribution of P-glycoprotein to efflux of ramosetron, a 5-HT3 receptor antagonist, across the blood-brain barrier. In: Journal of Pharmacy and Pharmacology. 2002 ; Vol. 54, No. 8. pp. 1055-1063.
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AU - Takanaga, H.

AU - Matsuo, H.

AU - Uchiumi, T.

AU - Kuwano, M.

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AU - Ohtani, H.

AU - Sawada, Y.

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N2 - 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 contribution of mdr1a, mdr1b and MDR1 P-glycoprotein by using LV500 cells, MBEC4 cells and LL-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.

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