| RRC ID |
41660
|
| Author |
Yamamoto C, Murakami H, Koyabu N, Takanaga H, Matsuo H, Uchiumi T, Kuwano M, Naito M, Tsuruo T, Ohtani H, Sawada Y.
|
| Title |
Contribution of P-glycoprotein to efflux of ramosetron, a 5-HT3 receptor antagonist, across the blood-brain barrier.
|
| Journal |
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.
|
| Volume |
54(8)
|
| Pages |
1055-63
|
| Published |
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
|
| Times Cited |
25
|
|
WOS Category
|
PHARMACOLOGY & PHARMACY
|
| Resource |
| Human and Animal Cells |
LLC-GA5-COL300(RCB0872) |
