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Received for publication April 18, 2005.
Revised June 23, 2005.
Accepted for publication July 6, 2005.
A clinical drug-drug interaction between famotidine (a H2 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 H2 receptor antagonists (cimetidine, famotidine, ranitidine) by rat and human basolateral organic anion and cation transporters (hOAT1, hOAT2, r/hOAT3, rOct1, r/hOCT2) were compared using their cDNA transfectants. The transport activity (Vmax/Km) of famotidine by rOat3 was 8- and 15-fold lower than that of cimetidine (Km: 91µM) and ranitidine (Km: 155µM), respectively, while that by hOAT3 (Km: 124µM) was 3-fold lower than that of cimetidine (Km: 149µM), but similar to that of ranitidine (Km: 234µM). 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 (Km: 396µM). rOct1 accepts all the H2 receptor antagonists with a similar activity, while the transport activities of ranitidine (Km: 61/56µM) and famotidine by r/hOCT2 were markedly lower than that of cimetidine (Km: 69/73µM). Probenecid was a potent inhibitor of r/OAT3 (Ki: 2.6- 5.8µM), 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.
Key words:
H2 receptor antagonists, OAT, OCT, drug-drug interaction, renal uptake, species difference
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