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

In-situ rat and mouse brain perfusion data indicated that the brain distribution of ramosetron (R-ramosetron), a 5-hydroxytryptamine(3) (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, ,dr1b 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 [C-14]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 [C-14]ramosetron by these cell lines. The uptake of [C-14]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 [C-14]ramosetron by MBEC4 cells. These indicate that the efflux of [C-14]ramosetron is partly mediated by mdr1a P-glycoprotein, but not by mdr1a P-glycoprotein. Further, [C-14]ramosetron was confirmed to be effluxed by human MDR1 P-glycoprotein. We conclude that the limited distribution of ramosetron to the brain is die, at least in part, to efflux mediated by the P-glycoprotein at the blood-brain barrier.