Nagata Yoshinori, Kusuhara Hiroyuki, Hirono Shuichi, Endou Hitoshi, Sugiyama Yuichi
Graduate School of Pharmaceutical Sciences, the University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Drug Metab Dispos. 2004 Sep;32(9):1040-7.
The choroid plexus (CP) acts as a site for the elimination of xenobiotic organic compounds from the cerebrospinal fluid (CSF). The purpose of the present study is to investigate the role of rat organic anion transporter 3 (rOat3; Slc22a8) in the uptake of H(2)-receptor antagonists (cimetidine, ranitidine, and famotidine) by the isolated rat CP. Saturable uptake of cimetidine and ranitidine was observed in rOat3-LLC with K(m) values of 80 and 120 microM, respectively, whereas famotidine was found to be a poor substrate. The steady-state concentration of the H(2)-receptor antagonists in the CSF was significantly increased by simultaneously administered probenecid, although it did not affect their brain and plasma concentrations. Saturable uptake of cimetidine and ranitidine was observed in the isolated rat CP with K(m) values of 93 and 170 microM, respectively, whereas 50% of the uptake of famotidine remained at the highest concentration examined (1 mM). The K(i) value of ranitidine for the uptake of cimetidine by the isolated CP (50 microM) was similar to its own K(m) value, suggesting that they share the same transporter for their uptake. The inhibition potency of organic anions such as benzylpenicillin, estradiol 17beta-glucuronide, p-aminohippurate, and estrone sulfate for the uptake of cimetidine by the isolated rat CP was similar to that for benzylpenicillin, the uptake of which has been hypothesized to be mediated by rOat3, whereas a minimal effect by tetraethylammonium excludes involvement of organic cation transporter(s). These results suggest that rOat3 is the most likely candidate transporter involved in regulating the CSF concentration of H(2)-receptor antagonists at the CP.
脉络丛（CP）是脑脊液（CSF）中外源性有机化合物的清除部位。本研究的目的是探讨大鼠有机阴离子转运体3（rOat3；Slc22a8）在分离的大鼠脉络丛摄取H₂受体拮抗剂（西咪替丁、雷尼替丁和法莫替丁）中的作用。在rOat3-LLC细胞中观察到西咪替丁和雷尼替丁的饱和摄取，其米氏常数（Kₘ）值分别为80和120 μM，而法莫替丁被发现是一种较差的底物。同时给予丙磺舒可显著提高脑脊液中H₂受体拮抗剂的稳态浓度，尽管它不影响其脑内和血浆浓度。在分离的大鼠脉络丛中观察到西咪替丁和雷尼替丁的饱和摄取，其Kₘ值分别为93和170 μM，而在检测的最高浓度（1 mM）下，法莫替丁的摄取仍有50%。雷尼替丁对分离的脉络丛摄取西咪替丁的抑制常数（Kᵢ）值（50 μM）与其自身的Kₘ值相似，表明它们的摄取共用同一转运体。有机阴离子如苄青霉素、17β-雌二醇葡萄糖醛酸苷、对氨基马尿酸和硫酸雌酮对分离的大鼠脉络丛摄取西咪替丁的抑制效力与对苄青霉素摄取的抑制效力相似，苄青霉素的摄取被推测由rOat3介导，而四乙铵的影响极小，排除了有机阳离子转运体的参与。这些结果表明，rOat3最有可能是参与调节脉络丛处H₂受体拮抗剂脑脊液浓度的转运体。
