TY - JOUR T1 - CARRIER-MEDIATED UPTAKE OF H<sub>2</sub>-RECEPTOR ANTAGONISTS BY THE RAT CHOROID PLEXUS: INVOLVEMENT OF RAT ORGANIC ANION TRANSPORTER 3 JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1040 LP - 1047 VL - 32 IS - 9 AU - Yoshinori Nagata AU - Hiroyuki Kusuhara AU - Shuichi Hirono AU - Hitoshi Endou AU - Yuichi Sugiyama Y1 - 2004/09/01 UR - http://dmd.aspetjournals.org/content/32/9/1040.abstract N2 - 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 H2-receptor antagonists (cimetidine, ranitidine, and famotidine) by the isolated rat CP. Saturable uptake of cimetidine and ranitidine was observed in rOat3-LLC with Km values of 80 and 120 μM, respectively, whereas famotidine was found to be a poor substrate. The steady-state concentration of the H2-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 Km values of 93 and 170 μM, respectively, whereas 50% of the uptake of famotidine remained at the highest concentration examined (1 mM). The Ki value of ranitidine for the uptake of cimetidine by the isolated CP (50 μM) was similar to its own Km value, suggesting that they share the same transporter for their uptake. The inhibition potency of organic anions such as benzylpenicillin, estradiol 17β-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 H2-receptor antagonists at the CP. The American Society for Pharmacology and Experimental Therapeutics ER -