Rifamycin SV and rifampicin exhibit differential inhibition of the hepaticrat organic anion transporting polypeptides, Oatp1 and Oatp2

The antibiotics, rifamycin SV and rifampicin, are known to interfere with h epatic bile salt and organic anion uptake. The aim of this study was to exp lore which transport systems are affected. In short-term-cultured rat hepat ocytes, low concentrations (10 mu mol/L) of both compounds inhibited mainly sodium-independent taurocholate uptake, whereas higher concentrations (100 mu mol/L) also inhibited sodium-dependent taurocholate uptake. In Xenopus laevis oocytes expressing the Na+/taurocholate cotransporting polypeptide ( Ntcp), high rifamycin SV and rifampicin concentrations were required for in hibition of taurocholate uptake. In contrast, sodium-independent taurochola te uptake mediated by the organic anion transporting polypeptides, Oatp1 an d Oatp2, was already substantially inhibited by 10 mu mol/L rifamycin SV. R ifampicin potently inhibited Oatp2-mediated taurocholate uptake, but did no t interfere with Oatp1-mediated taurocholate uptake. Similar effects of rif amycin SV and rifampicin were found for Oatp1- and Oatp2-mediated estradiol -17 beta-glucuronide transport. Dixon plot analysis yielded a pattern compa tible with competitive inhibition of estradiol-17 beta-glucuronide transpor t with K-i estimates of 6.6 mu mol/L and 7.3 mu mol/L for rifamycin SV-indu ced inhibition of Oatp1 and Oatp2, respectively, and of 1.4 mu mol/L for ri fampicin-induced inhibition of Oatp2. These results demonstrate that rifamy cin SV and rifampicin exhibit differential inhibition on Oatp1 and Oatp2, a nd identify rifampicin as a selective Oatp2 inhibitor. The data indicate th at these inhibitors can be used to determine the in vivo relevance of Oatp1 and Oatp2 for the overall bioavailability and disposition of drugs and oth er Oatp1/2, substrates.