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

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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 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.

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