二甲双胍和SGLT2抑制剂单独和联合的药代动力学特征:Wistar大鼠的药代动力学研究

M. Millan Fachi, Bruna Carolina Lui Dias, Jonata Augusto de Oliveria, Rosângela Gonçalves Peccinini, R. Pontarolo, M. D. de Campos
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引用次数: 0

摘要

目的:为了实现血糖控制,最终需要联合用药,尤其是SGLT2抑制剂与二甲双胍的双重治疗。尽管联合治疗的价值,了解药代动力学性质是至关重要的。因此,本研究旨在对降糖药进行联合和分离给药,了解其药代动力学特性。方法:采用灌胃法将25只大鼠分为5组:单用二甲双胍(60 mg/kg)、单用卡格列净20 mg/kg、卡格列净与二甲双胍(分别为20 mg/kg和60 mg/kg)、单用达格列净2 mg/kg、达格列净与二甲双胍(分别为2 mg/kg和60 mg/kg)。在给药后0.25 ~ 36小时采集血样,采用HPLC-MS/MS法定量。结果:二甲双胍联合达格列净组的Cmax (3400 ng/mL)、AUC (872.4 ng.min/L)和CL/F (72 mL/min/kg)较单用二甲双胍组的Cmax (523 ng/mL)、AUC (106.8 ng.min/L)和CL/F (752 mL/min/kg)有显著变化。对于canagliflozin,本研究Cmax为6116.7 ng/mL,与文献相似,但清除率(5.1 mL/min/kg)高于文献的3.5 mL/min/kg。报道的dapagliflozin CL/F清除率为3.33 mL/min/kg,而我们的结果为4.6 mL/min/kg。同一项研究还发表了达格列净的半衰期和MRT,比我们的研究结果略低。总的来说,卡格列净和达格列净的参数与文献相似,不随与二甲双胍同时给药而改变。结论:达格列净显著改变了二甲双胍的药动学配置,而二甲双胍共给药对SGLT2抑制剂的药动学无影响
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Pharmacokinetic Profile of Metformin and SGLT2 Inhibitors alone and in Combination: a Pharmacokinetic Study in Wistar Rats
Objective: To achieve glycemic control, a combination of drugs is eventually necessary, especially the dual therapy of SGLT2 inhibitors with metformin. Despite the value of combination therapy, understanding the pharmacokinetic properties is critical. Therefore, this study aimed to conduct the combined and isolated administration of hypoglycemic drugs to understand their pharmacokinetic properties. Methodology: The study was performed by gavage in twenty-five rats that were divided into five groups: metformin alone (60 mg/kg), canagliflozin alone 20 mg/kg, canagliflozin and metformin (20 mg/kg and 60 mg/kg, respectively), dapagliflozin alone 2 mg/kg, and dapagliflozin and metformin (2 mg/kg and 60 mg/kg, respectively). Blood samples were collected between 0.25 and 36 hours postdose and quantified by an HPLC-MS/MS method. Results: The metformin pharmacokinetics showed values lower than those from literature, but the most relevant result was a significant change in Cmax (3400 ng/mL), AUC (872.4 ng.min/L) and CL/F (72 mL/min/kg) in the metformin with dapagliflozin group compared to metformin alone Cmax (523 ng/mL), AUC (106.8 ng.min/L) and CL/F (752 mL/min/kg). For canagliflozin, the Cmax of 6116.7 ng/mL observed in our study was similar to that observed in literature, while the clearance (5.1 mL/min/kg) was higher than that of literature, which was 3.5 mL/min/kg. Clearance of dapagliflozin CL/F was reported as 3.33 mL/min/kg, while our result was 4.6 mL/min/kg. The same study also published dapagliflozin half-life and MRT, which were slightly lower than our findings. In general, the parameters of canagliflozin and dapagliflozin were similar to the literature and did not change with simultaneous administration with metformin. Conclusion: Dapagliflozin significantly changed the pharmacokinetic disposition of metformin, while metformin coadministration had no influence on the pharmacokinetics of SGLT2 inhibitors
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