A species difference in the transport activities of H2 receptor antagonists by rat and human renal organic anion and cation transporters

被引:141
作者
Tahara, H
Kusuhara, H
Endou, H
Koepsell, H
Imaoka, T
Fuse, E
Sugiyama, Y [1 ]
机构
[1] Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan
[2] Kyowa Hakko Kogyo Co Ltd, Drug Dev Res Labs, Pharmaceut Res Inst, Shizuoka, Japan
[3] Kyorin Univ, Sch Med, Dept Pharmacol & Toxicol, Mitaka, Tokyo, Japan
[4] Univ Wurzburg, Inst Atom & Zellbiol, Wurzburg, Germany
关键词
D O I
10.1124/jpet.105.088104
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
A clinical drug-drug interaction between famotidine (a H-2 receptor antagonist) and probenecid has not been reproduced in rats. The present study hypothesized that the species-dependent probenecid sensitivity is due to a species difference in the contribution of renal organic anion and cation transporters. The transport activities of the H-2 receptor antagonists ( cimetidine, famotidine, and ranitidine) by rat and human basolateral organic anion and cation transporters [human organic anion transporter (hOAT) 1, hOAT2, r/hOAT3, rat organic cation transporter (rOct) 1, and r/hOCT2] were compared using their cDNA transfectants. The transport activities (V-max/K-m) of famotidine (K-m, 345 mu M) by rOat3 were 8- and 15-fold lower than those of cimetidine (K-m, 91 mu M) and ranitidine (K-m, 155 mu M), respectively, whereas the activity by hOAT3 (K-m, 124 mu M) was 3-fold lower than that of cimetidine (K-m, 149 mu M) but similar to that of ranitidine (K-m, 234 mu M). Comparison of the relative transport activity with regard to that of cimetidine suggests that famotidine was more efficiently transported by hOAT3 than rOat3, and vice versa, for ranitidine. Only ranitidine was efficiently transported by hOAT2 (K-m, 396 mu M). rOct1 accepts all of the H-2 receptor antagonists with a similar activity, whereas the transport activities of ranitidine and famotidine (K-m, 61/56 mu M) by r/hOCT2 were markedly lower than that of cimetidine (K-m, 69/73 mu M). Probenecid was a potent inhibitor of r/OAT3 (K-i, 2.6-5.8 mu M), whereas it did not interact with OCTs. These results suggest that, in addition to the absence of OCT1 in human kidney, a species difference in the transport activity by hOAT3 and rOat3 accounts, at least in part, for the species difference in the drug-drug interaction between famotidine and probenecid.
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页码:337 / 345
页数:9
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