Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver

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Abstract

The antibiotics rifamycin SV and rifampicin substantially reduce sulfobromophthalein (BSP) elimination in humans. In rats, rifamycin SV and rifampicin were shown to interfere with hepatic organic anion uptake by inhibition of the organic anion transporting polypeptides Oatp1 and Oatp2. Therefore, we investigated the effects of rifamycin SV and rifampicin on the OATPs of human liver and determined whether rifampicin is a substrate of 1 or several of these carriers. In complementary RNA (cRNA)-injected Xenopus laevis oocytes, rifamycin SV (10 μmol/L) cis-inhibited human organic anion transporting polypeptide C (SLC21A6) (OATP-C), human organic anion transporting polypeptide 8 (SLC21A8) (OATP8), human organic anion transporting polypeptide B (SLC21A9) (OATP-B), and human organic anion transporting polypeptide A (SLC21A3) (OATP-A) mediated BSP uptake by 69%, 79%, 89%, and 57%, respectively, as compared with uptake into control oocytes. In the presence of 100 μmol/L rifamycin SV, BSP uptake was almost completely abolished. Approximate Ki values were 2 μmol/L for OATP-C, 3 μmol/L for OATP8, 3 μmol/L for OATP-B and 11 μmol/L for OATP-A. Rifampicin (10 μmol/L) inhibited OATP8-mediated BSP uptake by 50%, whereas inhibition of OATP-C–, OATP-B–, and OATP-A–mediated BSP transport was below 15%. 100 μmol/L rifampicin inhibited OATP-C– and OATP8-, OATP-B– and OATP-A–mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding Ki values were 17 μmol/L for OATP-C, 5 μmol/L for OATP8, and 51 μmol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent Km value 13 μmol/L) and OATP8 (2.3 μmol/L). In conclusion, these results show that rifamycin SV and rifampicin interact with OATP-mediated substrate transport to different extents. Inhibition of human liver OATPs can explain the previously observed effects of rifamycin SV and rifampicin on hepatic organic anion elimination.

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