Zhang Guoqiang, Ma Yanrong, Xi Dali, Rao Zhi, Sun Xiaohan, Wu Xin'an
Department of Pharmacy, the First Hospital of Lanzhou University, Lanzhou, 730000, China.
Department of Pathology, the First Hospital of Lanzhou University, Lanzhou, 730000, China.
Biopharm Drug Dispos. 2019 Jan;40(1):3-11. doi: 10.1002/bdd.2164. Epub 2018 Dec 18.
Metformin is always used as the baseline antidiabetic therapy for patients with type 2 diabetes mellitus (T2DM) and hyperuricemia. Metformin is excreted into urine through active secretion mediated by rOCTs and rMATE1.The aim of this study was to identify the effects of high uric acid on the disposition and its mechanism. For the in vivo study, a hyperuricemic animal model was induced by intraperitoneal injection of potassium oxonate (250 mg/kg) in rats. Metformin (100 mg/kg) was administered orally to investigate the pharmacokinetics in control and hyperuricemic rats, respectively. For the in vitro study, HEK293 and HepaRG cells were used to investigate the effect of uric acid (15 mg/dl) on the expression of OCT1, OCT2 and MATE1 and the disposition of metformin, respectively. The in vivo study showed that the AUC of metformin was significantly decreased by 33.3%, whereas the cumulative urinary excretion of metformin was increased by 25.4% in hyperuricemic rats compared with that in control rats. The renal rOCT1, rOCT2 and rMATE1 and hepatic rMATE1 levels were increased in hyperuricemic rats compared with those in control rats, respectively. The in vitro study showed that uric acid could upregulate the expression of OCT2 and MATE1 in HEK293 cells and MATE1 in HepaRG cells and increase the intracellular metformin concentration in these two cell lines. These results demonstrated that a high uric acid level promoted urinary metformin excretion and decreased the plasma metformin concentration; the in vivo and in vitro studies provided a possible explanation being that high uric acid could upregulate the expression of renal metformin transporters OCTs and MATE1.
二甲双胍一直被用作2型糖尿病（T2DM）合并高尿酸血症患者的基础抗糖尿病治疗药物。二甲双胍通过rOCTs和rMATE1介导的主动分泌排泄到尿液中。本研究的目的是确定高尿酸对其处置的影响及其机制。在体内研究中，通过腹腔注射草酸钾（250 mg/kg）诱导大鼠高尿酸血症动物模型。分别口服给予二甲双胍（100 mg/kg）以研究对照大鼠和高尿酸血症大鼠的药代动力学。在体外研究中，分别使用HEK293和HepaRG细胞研究尿酸（15 mg/dl）对OCT1、OCT2和MATE1表达以及二甲双胍处置的影响。体内研究表明，与对照大鼠相比，高尿酸血症大鼠中二甲双胍的AUC显著降低33.3%，而二甲双胍的累积尿排泄量增加25.4%。与对照大鼠相比，高尿酸血症大鼠的肾脏rOCT1、rOCT2和rMATE1以及肝脏rMATE1水平分别升高。体外研究表明，尿酸可上调HEK293细胞中OCT2和MATE1以及HepaRG细胞中MATE1的表达，并增加这两种细胞系中的细胞内二甲双胍浓度。这些结果表明，高尿酸水平促进了二甲双胍的尿排泄并降低了血浆二甲双胍浓度；体内和体外研究提供了一个可能的解释，即高尿酸可上调肾脏二甲双胍转运体OCTs和MATE1的表达。
