Received for publication December 18, 2006.
Revised February 1, 2007.
Accepted for publication February 8, 2007.

The influence of macrolide antibiotics on the uptake of organic anions and drugs mediated by OATP1B1 and OATP1B3

Abstract

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

Key words: antibiotics, drug interactions, hepatic uptake, hepatobiliary transport, membrane transport, organic anion transport, transporters

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