title: Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver.
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 micromol/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 micromol/L rifamycin SV, BSP uptake was almost completely abolished. Approximate K(i) values were 2 micromol/L for OATP-C, 3 micromol/L for OATP8, 3 micromol/L for OATP-B and 11 micromol/L for OATP-A. Rifampicin (10 micromol/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 micromol/L rifampicin inhibited OATP-C- and OATP8-, OATP-B- and OATP-A-mediated BSP uptake by 66%, 96%, 25%, and 49%, respectively. The corresponding K(i) values were 17 micromol/L for OATP-C, 5 micromol/L for OATP8, and 51 micromol/L for OATP-A. Direct transport of rifampicin could be shown for OATP-C (apparent K(m) value 13 micromol/L) and OATP8 (2.3 micromol/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.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Department of Medicine, University Hospital, CH-8091 Zürich, Switzerland.
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Vavricka
authors.forename: Jessica
authors.initials: J
authors.lastname: Van Montfoort
authors.forename: Huy Riem
authors.initials: HR
authors.lastname: Ha
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Meier
authors.forename: Karin
authors.initials: K
authors.lastname: Fattinger
mesh_terms: D000818:Animals; D000904:Antibiotics, Antitubercular / Q000494:pharmacology*; D001667:Binding, Competitive; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007202:Indicators and Reagents; D008099:Liver / Q000187:drug effects* / Q000378:metabolism*; D027381:Liver-Specific Organic Anion Transporter 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D018075:RNA, Complementary; D011994:Recombinant Proteins; D012293:Rifampin / Q000378:metabolism / Q000494:pharmacology*; D012294:Rifamycins / Q000494:pharmacology*; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013448:Sulfobromophthalein / Q000378:metabolism; D014162:Transfection; D014982:Xenopus laevis
chemical_list: D000904:Antibiotics, Antitubercular; D007202:Indicators and Reagents; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D018075:RNA, Complementary; D011994:Recombinant Proteins; D012294:Rifamycins; C421209:SLCO1B3 protein, human; C450859:SLCO2B1 protein, human; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013448:Sulfobromophthalein; C023808:rifamycin SV; D012293:Rifampin