Markowicz-Piasecka Magdalena, Huttunen Kristiina M, Mikiciuk-Olasik Elżbieta, Sikora Joanna
Laboratory of Bioanalysis, Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Medical University of Lodz, ul. Muszyńskiego1, 90-151 Lodz, Poland.
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Yliopistonranta 1C, POB 1627, 70211 Kuopio, Finland.
Chem Biol Interact. 2018 Jan 25;280:15-27. doi: 10.1016/j.cbi.2017.12.005. Epub 2017 Dec 5.
As the pharmacokinetic properties of metformin are unfavourable, several analogues and prodrugs have been synthesised to improve its bioavailability. The aim of this study was to assess the plasma stability of sulfenamide and sulfonamide derivatives of metformin and establish their effects on plasma haemostasis and integrity of red blood cells (RBCs). The overall haemostasis potential was evaluated spectrophotometrically by clot formation and lysis test (CL-test). PT (Prothrombin Time) and APTT (Activated Partial Tromboplastin Time) were used to evaluate the effects if the compounds on the extrinsic and intrinsic coagulation pathway. Haemolysis assay, microscopy and flow cytometry studies were conducted to determine the effect of the compounds on RBCs. Two sulfonamide and one sulfenamide derivatives of metformin were associated with a statistically significant decrease in the overall potential of clot formation and fibrinolysis (↓ CL), suggesting that these compounds may exert beneficial effects regarding plasma haemostasis, which is frequently impaired in diabetic patients. p- and o-Nitrobenzene sulfonamides contributed to the beneficial change in kinetic parameters of clot formation and fibrinolysis. o-Nitrobenzene sulfonamide significantly increased thrombin generation time (↑ TGt) and was also found to prolong both APTT and PT. All compounds did not exert any effects on the integrity of RBCs over the concentration range 0.006-0.6 μmol/mL which constitutes the expected therapeutic concentration. In conclusion, sulfonamide derivatives of metformin present potentially beneficial properties in terms of plasma haemostasis which is frequently impaired in T2DM patients. Therefore, metformin sulfonamides may become a prototype for further design and synthesis of novel metformin analogues and prodrugs with improved pharmacokinetic properties.
由于二甲双胍的药代动力学性质不佳，已合成了几种类似物和前药以提高其生物利用度。本研究的目的是评估二甲双胍的亚磺酰胺和磺酰胺衍生物的血浆稳定性，并确定它们对血浆止血和红细胞（RBC）完整性的影响。通过凝血形成和溶解试验（CL试验）用分光光度法评估整体止血潜力。使用凝血酶原时间（PT）和活化部分凝血活酶时间（APTT）来评估这些化合物对外源性和内源性凝血途径的影响。进行溶血试验、显微镜检查和流式细胞术研究以确定这些化合物对红细胞的影响。二甲双胍的两种磺酰胺和一种亚磺酰胺衍生物与凝血形成和纤维蛋白溶解的整体潜力在统计学上显著降低有关（CL降低），这表明这些化合物可能对血浆止血产生有益影响，而血浆止血在糖尿病患者中经常受损。对硝基苯磺酰胺和邻硝基苯磺酰胺有助于凝血形成和纤维蛋白溶解动力学参数的有益变化。邻硝基苯磺酰胺显著增加凝血酶生成时间（TGt增加），并且还发现它延长了APTT和PT。在构成预期治疗浓度的0.006 - 0.6 μmol/mL浓度范围内，所有化合物对红细胞的完整性均无任何影响。总之，二甲双胍的磺酰胺衍生物在血浆止血方面具有潜在的有益特性，而血浆止血在2型糖尿病患者中经常受损。因此，二甲双胍磺酰胺可能成为进一步设计和合成具有改善药代动力学性质的新型二甲双胍类似物和前药的原型。
