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

Research output: Contribution to journalArticle

28 Citations (Scopus)

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 - 2002 Aug 29
Externally publishedYes

    Fingerprint

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

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, 54(8), 1055-1063. https://doi.org/10.1211/002235702320266208