The Influence of Macrolide Antibiotics on the Uptake of Organic Anions and Drugs Mediated by OATP1B1 and OATP1B3

• DOI: 10.1124/dmd.106.014407
• Publication Date: 2007-02-13T01:10:18Z
• Authors: Annick Seithel; Sonja Eberl; Katrin Singer; Daniel Auge; Georg Heinkele; Nadine B. Wolf; Frank Dörje; Martin F. Fromm; Jörg König
• Keywords: Roxithromycin; Cerivastatin

Macrolides may cause severe drug interactions due to the inhibition of metabolizing enzymes. Transporter-mediated uptake drugs into cells [e.g., by members human organic anion transporting polypeptide (OATP) family] is a determinant disposition and prerequisite for subsequent metabolism. However whether macrolides are also inhibitors transporters, thereby providing an additional mechanism interactions, has not been systematically studied. The OATP family OATP1B1 OATP1B3 mediate endogenous substances such as antibiotics HMG-CoA reductase (statins) hepatocytes. In this study we investigated potential role these transporters on macrolide-induced interactions. By using sulfobromophthalein (BSP) inhibitor pravastatin substrates, effects azithromycin, clarithromycin, erythromycin, roxithromycin ketolide telithromycin OATP1B1- OATP1B3-mediated were analyzed. These experiments demonstrated that BSP can be inhibited increasing concentrations all except azithromycin. IC₅₀ values 11 μM telithromycin, 32 34 37 roxithromycin. lower than OATP1B1-mediated (96–217 μM). in concentration-dependent manner pravastatin. summary, results indicate alterations transporter function certain macrolides/ketolides have considered underlying drug-drug