The influence of macrolide antibiotics on the uptake of organic anions and drugs mediated by OATP1B1 and OATP1B3
The influence of macrolide antibiotics on the uptake of organic anions and drugs mediated by OATP1B1 and OATP1B3
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DOI：
10.1124/dmd.106.014407
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发表时间：
2007-05-01
影响因子：
3.9
通讯作者：
Koenig, Joerg
中科院分区：
文献类型：
--
作者：
Seithel, Annick;Eberl, Sonja;Koenig, Joerg
大环内酯类药物由于抑制代谢酶而可能引起严重的药物相互作用。转运蛋白介导的药物摄取进入细胞[例如，由人有机阴离子转运多肽（OATP）家族的成员]是药物处置的决定因素和随后代谢的先决条件。然而，大环内酯类是否也是摄取转运蛋白的抑制剂，从而提供了一个额外的药物相互作用机制，还没有系统地研究。人OATP家族成员OATP 1B 1和OATP 1B 3介导内源性物质和药物（如抗生素和HMG-CoA还原酶抑制剂（他汀类药物））摄入肝细胞。在这项研究中，我们研究了这些摄取转运蛋白对大环内酯类药物相互作用的潜在作用。通过使用磺溴酞（BSP）和HMG-CoA还原酶抑制剂普伐他汀作为底物，分析了大环内酯类阿奇霉素、克拉霉素、红霉素和罗红霉素以及酮内酯泰利霉素对OATP 1B 1和OATP 1B 3介导的摄取的影响。这些实验表明，OATP 1B 1和OATP 1B 3介导的BSP和普伐他汀摄取可被增加浓度的所有大环内酯类药物（阿奇霉素除外）抑制。泰利霉素、克拉霉素、红霉素和罗红霉素抑制OATP 1B 3介导的BSP摄取的IC 50值分别为11 μ M、32 μ M、34 μ M和37 μ M。这些IC 50值低于抑制OATP 1B 1介导的BSP摄取的IC 50值（96-217 μ M）。这些大环内酯类药物还以浓度依赖性方式抑制OATP 1B 1和OATP 1B 3介导的普伐他汀摄取。总之，这些结果表明，某些大环内酯类/酮内酯类的摄取转运蛋白功能的改变必须被视为药物相互作用的潜在额外机制。
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 IC50 values for the inhibition of OATP1B3-mediated BSP uptake were 11 mu M for telithromycin, 32 mu M for clarithromycin, 34 mu M for erythromycin, and 37 mu M for roxithromycin. These IC50 values were lower than the IC50 values for inhibition of OATP1B1-mediated BSP uptake (96-217 mu M). These macrolides also inhibited in a concentration-dependent manner the OATP1B1and 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.