Abstract

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, 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 μM) by rOat3 were 8- and 15-fold lower than those of cimetidine (K_m, 91 μM) and ranitidine (K_m, 155 μM), respectively, whereas the activity by hOAT3 (K_m, 124 μM) was 3-fold lower than that of cimetidine (K_m, 149 μM) but similar to that of ranitidine (K_m, 234 μM). 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 μM). rOct1 accepts all of the H₂ receptor antagonists with a similar activity, whereas the transport activities of ranitidine and famotidine (K_m, 61/56 μM) by r/hOCT2 were markedly lower than that of cimetidine (K_m, 69/73 μM). Probenecid was a potent inhibitor of r/OAT3 (K_i, 2.6-5.8 μM), 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.