Te Brake Lindsey H M, van den Heuvel Jeroen J M W, Buaben Aaron O, van Crevel Reinout, Bilos Albert, Russel Frans G, Aarnoutse Rob E, Koenderink Jan B
Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
Department of Pharmacy, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
Antimicrob Agents Chemother. 2016 Nov 21;60(12):7105-7114. doi: 10.1128/AAC.01471-16. Print 2016 Dec.
It is largely unknown if simultaneous administration of tuberculosis (TB) drugs and metformin leads to drug-drug interactions (DDIs). Disposition of metformin is determined by organic cation transporters (OCTs) and multidrug and toxin extrusion proteins (MATEs). Thus, any DDIs would primarily be mediated via these transporters. This study aimed to assess the in vitro inhibitory effects of TB drugs (rifampin, isoniazid, pyrazinamide, ethambutol, amikacin, moxifloxacin, and linezolid) on metformin transport and whether TB drugs are also substrates themselves of OCTs and MATEs. HEK293 cells overexpressing OCT1, OCT2, OCT3, MATE1, and MATE2K were used to study TB drug-mediated inhibition of [C]metformin uptake and to test if TB drugs are transporter substrates. Metformin uptake was determined by quantifying [C]metformin radioactivity, and TB drug uptake was analyzed using liquid chromatography-tandem mass spectrometry. DDI indices were calculated (plasma maximum concentrations [C]/50% inhibitory concentrations [IC]), and based on the literature, a cutoff of >0.1 was assumed to warrant further in vivo investigation. Moxifloxacin was the only TB drug identified as a potent inhibitor (DDI index of >0.1) of MATE1- and MATE2K-mediated metformin transport, with ICs of 12 μM (95% confidence intervals [CI], 5.1 to 29 μM) and 7.6 μM (95% CI, 0.2 to 242 μM), respectively. Of all TB drugs, only ethambutol appeared to be a substrate of OCT1, OCT2, OCT3, MATE1, and MATE2K. MATE1-mediated ethambutol uptake was inhibited strongly (DDI index of >0.1) by moxifloxacin (IC, 12 μM [95% CI, 3.4 to 43 μM]). Our findings provide a mechanistic basis for DDI predictions concerning ethambutol. According to international guidelines, an in vivo interaction study is warranted for the observed in vitro interaction between ethambutol and moxifloxacin.
目前，对于同时服用抗结核药物和二甲双胍是否会导致药物相互作用（DDIs），人们知之甚少。二甲双胍的处置由有机阳离子转运体（OCTs）和多药及毒素外排蛋白（MATEs）决定。因此，任何药物相互作用主要通过这些转运体介导。本研究旨在评估抗结核药物（利福平、异烟肼、吡嗪酰胺、乙胺丁醇、阿米卡星、莫西沙星和利奈唑胺）对二甲双胍转运的体外抑制作用，以及抗结核药物本身是否也是OCTs和MATEs的底物。使用过表达OCT1、OCT2、OCT3、MATE1和MATE2K的HEK293细胞来研究抗结核药物介导的[C]二甲双胍摄取抑制作用，并测试抗结核药物是否为转运体底物。通过定量[C]二甲双胍放射性来确定二甲双胍摄取，使用液相色谱 - 串联质谱法分析抗结核药物摄取。计算药物相互作用指数（血浆最大浓度[C]/50%抑制浓度[IC]），并根据文献，假定截断值>0.1值得进一步进行体内研究。莫西沙星是唯一被确定为MATE1和MATE2K介导的二甲双胍转运的强效抑制剂（药物相互作用指数>0.1），其IC分别为12μM（95%置信区间[CI]，5.1至29μM）和7.6μM（95%CI，0.2至242μM）。在所有抗结核药物中，只有乙胺丁醇似乎是OCT1、OCT2、OCT3、MATE1和MATE2K的底物。莫西沙星强烈抑制MATE1介导的乙胺丁醇摄取（药物相互作用指数>0.1）（IC，12μM[95%CI，3.4至43μM]）。我们的研究结果为乙胺丁醇的药物相互作用预测提供了机制基础。根据国际指南，对于乙胺丁醇和莫西沙星之间观察到的体外相互作用，有必要进行体内相互作用研究。
