Carrier-mediated uptake of H2-receptor antagonists by the rat choroid plexus: involvement of rat organic anion transporter 3.
Carrier-mediated uptake of H2-receptor antagonists by the rat choroid plexus: involvement of rat organic anion transporter 3.
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发表时间：
2004-09
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通讯作者：
Yoshinori Nagata;H. Kusuhara;S. Hirono;H. Endou;Y. Sugiyama
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作者：
Yoshinori Nagata;H. Kusuhara;S. Hirono;H. Endou;Y. Sugiyama
脉络丛(CP)是从脑脊液(CSF)中清除外源有机化合物的场所。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CP摄取H(2)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中观察到西咪替丁和雷尼替丁的饱和吸收，K(M)分别为80和120微米，而法莫替丁是一个很差的底物。同时给予丙磺舒后，脑脊液中H(2)受体拮抗剂的稳态浓度显著增加，但不影响脑组织和血浆中的浓度。西咪替丁和雷尼替丁在分离的大鼠CP中可被饱和摄取，K(M)分别为93和170微米，而法莫替丁摄取的50%仍保持在所考察的最高浓度(1 MM)。雷尼替丁对分离的CP(50微米)摄取西咪替丁的K(I)值与其自身的K(M)值相似，表明两者摄取的转运体相同。有机阴离子如青霉素、雌二醇17β-葡萄糖醛酸脂、对氨基马尿酸和硫酸雌酮对大鼠CP摄取西咪替丁的抑制作用与青霉素相似，推测是由rOat3介导的，而四乙基铵的最小作用排除了有机阳离子转运体的参与(S)。这些结果表明，rOat3是最有可能参与调节脑脊液中H(2)受体拮抗剂浓度的候选转运体。
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.