Ma Yan-rong, Huang Jing, Shao Yun-yun, Ma Kang, Zhang Guo-qiang, Zhou Yan, Zhi Rao, Qin Hong-yan, Wu Xin-an
Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou 730000, China; School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou 730000, China.
Eur J Pharm Sci. 2015 Feb 20;68:18-26. doi: 10.1016/j.ejps.2014.12.002. Epub 2014 Dec 5.
Renal tubular secretion is an important pathway for the elimination of many clinically used drugs. Metformin, a commonly prescribed first-line antidiabetic drug, is secreted primarily by the renal tubule. Many patients with type 2 diabetes mellitus (T2DM) receiving metformin may together be given selective β1 blockers (e.g., atenolol). Therefore, it is of great use to evaluate the effect of atenolol on metformin urinary excretion for exploring drug interactions and predicting the adverse effect of drugs. The aim of this study was to investigate the effect of atenolol on the pharmacokinetic of metformin and plasma lactate (LCA) level in rats, for high LCA is a serious adverse reaction of metformin after long-term metformin treatment. In this study, rats were treated with metformin alone or in combination with atenolol. Plasma, urine and tissue concentration of metformin was determined by HPLC method, while Western blotting and immunohistochemical analysis were used to evaluate the renal expression of rat organic cation transporter 2 (rOct2) and multidrug and toxin extrusion protein 1 (rMate1). The results showed that, after 7 days drug treatment, the AUC0 → t of metformin in atenolol and metformin co-administration group was significantly increased by 19.5% compared to that in metformin group, while the 24h cumulative urinary excretion of metformin was significantly decreased by 57.3%. In addition, atenolol treatment significantly decreased the renal expression of rMate1, but had no effect on rOct2 expression, renal blood perfusion and glomerular filtration. Moreover, plasma LCA level in atenolol and metformin co-administration group was significantly increased by 83.3% compared to that in metformin group after 60 days drug treatment. These results indicated that atenolol can inhibit urinary excretion of metformin via decreasing renal rMate1 expression, and long-term atenolol and metformin co-administration may induce potential lactic acidosis. Our results, for the first time, provided an important experimental evidence that rMate1 is the target of transporter-mediated drug interactions concerning metformin and atenolol.
肾小管分泌是许多临床常用药物消除的重要途径。二甲双胍是一种常用的一线抗糖尿病药物，主要通过肾小管分泌。许多接受二甲双胍治疗的2型糖尿病（T2DM）患者可能同时服用选择性β1受体阻滞剂（如阿替洛尔）。因此，评估阿替洛尔对二甲双胍尿排泄的影响对于探索药物相互作用和预测药物不良反应具有重要意义。本研究的目的是探讨阿替洛尔对大鼠二甲双胍药代动力学及血浆乳酸（LCA）水平的影响，因为高LCA是长期服用二甲双胍后的一种严重不良反应。在本研究中，大鼠单独给予二甲双胍或与阿替洛尔联合给药。采用高效液相色谱法测定二甲双胍的血浆、尿液和组织浓度，同时采用蛋白质免疫印迹法和免疫组织化学分析法评估大鼠有机阳离子转运体2（rOct2）和多药及毒素外排蛋白1（rMate1）的肾脏表达。结果显示，药物治疗7天后，阿替洛尔与二甲双胍联合给药组二甲双胍的AUC0→t较二甲双胍组显著增加19.5%，而二甲双胍的24小时累积尿排泄量显著减少57.3%。此外，阿替洛尔治疗显著降低rMate1的肾脏表达，但对rOct2表达、肾血流量和肾小球滤过无影响。而且，药物治疗60天后，阿替洛尔与二甲双胍联合给药组的血浆LCA水平较二甲双胍组显著升高83.3%。这些结果表明，阿替洛尔可通过降低肾脏rMate1表达抑制二甲双胍的尿排泄，长期阿替洛尔与二甲双胍联合给药可能诱发潜在的乳酸性酸中毒。我们的结果首次提供了重要的实验证据，表明rMate1是二甲双胍和阿替洛尔转运体介导的药物相互作用的靶点。
