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

Abstract

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 whether macrolides are also inhibitors of uptake transporters, thereby providing an additional mechanism of drug interactions, has not been systematically studied. The human OATP family members OATP1B1 and OATP1B3 mediate the uptake of endogenous substances and drugs such as 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. By using sulfobromophthalein (BSP) and the HMG-CoA reductase inhibitor pravastatin as substrates, the effects of the macrolides azithromycin, clarithromycin, erythromycin, and roxithromycin and of the ketolide telithromycin on the OATP1B1-and OATP1B3-mediated uptake were 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 IC 50 values for the inhibition of OATP1B3-mediated BSP uptake were 11 M for telithromycin, 32 M for clarithromycin, 34 M for erythromycin, and 37 M for roxithromycin. These IC 50 values were lower than the IC 50 values for inhibition of OATP1B1-mediated BSP uptake (96-217 M). 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.Macrolide antibiotics (e.g., erythromycin and clarithromycin) can cause severe drug interactions by increasing plasma concentrations of simultaneously administered compounds. The major mechanism underlying these drug interactions is believed to be inhibition of the major drug metabolizing enzyme CYP3A4 in small intestine and liver (Wrington and Thummel, 2000;Ito et al., 2003;Polasek and Miners, 2006).Published data indicate that certain macrolides are also inhibitors of the apically/luminally localized drug efflux pump P-glycoprotein (Kim et al., 1999;Marzolini et al., 2004;Eberl et al., 2005). By inhibition of P-glycoprotein function they increase drug absorption from the gut lumen and decrease biliary elimination and renal secretion of concomitantly administered drugs such as the cardiac glycoside digoxin (Rengelshausen et al., 2003). This in turn leads to increased drug concentrations and drug toxicity.Newly recognized, additional determinants of drug disposition are uptake transporters of the OATP (SLCO) family (Hagenbuch and Meier, 2004;König et al., 2006). Members of the OATP family transport a wide range of drugs including HMG-CoA reductase inhibitors (cerivastatin, flu...

Expression of organic anion-transporting polypeptides 1B1 and 1B3 in ovarian cancer cells: Relevance for paclitaxel transport

“…Therefore, inter-individual expression levels of OATP1B1 and OATP1B3 in the basolateral membrane of hepatocytes might be responsible for differences in the occurrence of toxic side effects such as neutropenia, neuropathy and cardiac effects during paclitaxel therapy. Such drug-drug interactions have been reported for the OATP1B1 and OATP1B3 substrates pravastatine and bosentan [46,47] when concomitantly administered with clarithromycin and cyclosporine or rifampicin, respectively.…”

Targeting Effect of Traditional Chinese Medicine

“…Some drugs affected the activity of transporters and as a consequence affected the distribution of the substrate of transporters (S. Eberl et al, 2007;A.Y. Coban et al, 2004 ;A. Seithel, et al, 2007, Sikri et al, 2004.…”

The emerging role of transport systems in liver function tests

“…Erythromycin inhibits OATP1B1 and OATP1B3 (Seithel et al, 2007), is transported by OATP1B1 (Franke et al, 2008) and is a substrate for MRP2 (Franke et al, 2011) (table 1).…”