The incidence of hypertension in diabetic patients has been increasing and contributing to the high mortality of diabetic patients. Recently, verapamil use was found to lower fasting blood glucose levels in diabetic patients, which led to a new indication of verapamil as combination treatment with anti-diabetic agents such as metformin. As pharmacokinetic (PK) interaction can affect drug efficacy and safety in drug combination, their PK-based interaction is recommended to be evaluated in preclinical levels as well as clinical levels. In case of metformin and verapamil, organic cation transporter (OCT) 1 and 2 primarily mediate metformin distribution to the liver and its elimination into urine, whereas cytochrome P450 is responsible for the hepatic metabolism of verapamil. Verapamil is also known as a potential OCT2 inhibitor. Thus, PK interaction between metformin (30 mg/kg) and verapamil (20 mg/kg) were investigated after their simultaneous administration to rats. In our results, verapamil inhibited the OCT2-mediated renal excretion of metformin, subsequently leading to increase of the systemic exposure of metformin. In contrast, metformin did not influence the pharmacokinetic pattern of verapamil. Although the further clinical investigation is required, our finding suggests a possibility of OCT2-mediated interaction of metformin and verapamil.

中文翻译：

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二甲双胍和维拉帕米在大鼠中的药代动力学相互作用：维拉帕米对OCT2介导的二甲双胍肾排泄的抑制作用。

糖尿病患者中高血压的发病率一直在增加，并导致糖尿病患者的高死亡率。最近，发现维拉帕米的使用降低了糖尿病患者的空腹血糖水平，这导致了维拉帕米与抗糖尿病药如二甲双胍联合治疗的新迹象。由于药代动力学（PK）相互作用会影响药物联合用药的疗效和安全性，因此建议在临床前水平和临床水平评估其基于PK的相互作用。在二甲双胍和维拉帕米的情况下，有机阳离子转运蛋白（OCT）1和2主要介导二甲双胍向肝脏的分布及其向尿液中的清除，而细胞色素P450负责维拉帕米的肝代谢。维拉帕米也被称为潜在的OCT2抑制剂。从而，同时给予大鼠二甲双胍（30 mg / kg）和维拉帕米（20 mg / kg）之间的PK相互作用。在我们的研究结果中，维拉帕米抑制了OCT2介导的二甲双胍的肾脏排泄，从而导致二甲双胍的全身暴露增加。相反，二甲双胍不影响维拉帕米的药代动力学模式。尽管需要进行进一步的临床研究，但我们的发现提示OCT2介导的二甲双胍与维拉帕米相互作用的可能性。二甲双胍不影响维拉帕米的药代动力学模式。尽管需要进行进一步的临床研究，但我们的发现提示OCT2介导的二甲双胍与维拉帕米相互作用的可能性。二甲双胍不影响维拉帕米的药代动力学模式。尽管需要进行进一步的临床研究，但我们的发现提示OCT2介导的二甲双胍与维拉帕米相互作用的可能性。