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-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.
Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Chika
C
Yamamoto
Hideyasu
H
Murakami
Noriko
N
Koyabu
Hitomi
H
Takanaga
Hirotami
H
Matsuo
Takeshi
T
Uchiumi
Michihiko
M
Kuwano
Mikihiko
M
Naito
Takashi
T
Tsuruo
Hisakazu
H
Ohtani
Yasufumi
Y
Sawada
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000494:pharmacology*; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000494:pharmacology*; D018528:ATP-Binding Cassette Transporters / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000493:pharmacokinetics*; D001812:Blood-Brain Barrier; D002250:Carbon Radioisotopes; D002460:Cell Line; D018432:Drug Resistance, Multiple; D008297:Male; D051379:Mice; D051381:Rats; D017208:Rats, Wistar; D012702:Serotonin Antagonists / Q000493:pharmacokinetics*
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D001562:Benzimidazoles; D002250:Carbon Radioisotopes; D012702:Serotonin Antagonists; C071315:ramosetron; C095122:multidrug resistance protein 3