Tahara Atsuo, Takasu Toshiyuki, Yokono Masanori, Imamura Masakazu, Kurosaki Eiji
Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan.
J Pharmacol Sci. 2016 Jul;131(3):198-208. doi: 10.1016/j.jphs.2016.06.004. Epub 2016 Jun 29.
Previously we investigated the pharmacokinetic, pharmacodynamic, and pharmacologic properties of all six sodium-glucose cotransporter (SGLT) 2 inhibitors commercially available in Japan using normal and diabetic mice. We classified the SGLT2 inhibitors with respect to duration of action as either long-acting (ipragliflozin and dapagliflozin) or intermediate-acting (tofogliflozin, canagliflozin, empagliflozin, and luseogliflozin). In the present study, antidiabetic effects of repeated administration of these SGLT2 inhibitors in type 2 diabetic mice were investigated. When repeatedly administered for 4 weeks, all SGLT2 inhibitors significantly exhibited antihyperglycemic, antihyperinsulinemic, and pancreas-protective effects, as well as insulin resistance-improving effects. When compared at doses producing comparable reduction in hyperglycemia across all drugs, the antidiabetic effects of ipragliflozin and dapagliflozin were more potent than those of the other four drugs, but these differences among the six drugs were not statistically significant. Further, an oral glucose tolerance test performed after repeated administration demonstrated significant improvement in glucose tolerance only with ipragliflozin and dapagliflozin, implying improved insulin resistance and secretion. Taken together, these findings demonstrate that, although all SGLT2 inhibitors exert antidiabetic effects in type 2 diabetic mice, these pharmacologic effects might be slightly superior with the long-acting drugs, which are able to provide favorable blood glucose control throughout the day.
此前，我们使用正常小鼠和糖尿病小鼠，研究了日本市售的所有六种钠-葡萄糖协同转运蛋白（SGLT）2抑制剂的药代动力学、药效动力学和药理学特性。我们根据作用持续时间将SGLT2抑制剂分为长效（依帕列净和达格列净）或中效（托格列净、卡格列净、恩格列净和鲁格列净）两类。在本研究中，我们研究了在2型糖尿病小鼠中重复给药这些SGLT2抑制剂的抗糖尿病作用。当连续给药4周时，所有SGLT2抑制剂均显著表现出降血糖、降高胰岛素血症和胰腺保护作用，以及改善胰岛素抵抗的作用。当在所有药物中产生相当程度高血糖降低的剂量下进行比较时，依帕列净和达格列净的抗糖尿病作用比其他四种药物更强，但这六种药物之间的差异无统计学意义。此外，重复给药后进行的口服葡萄糖耐量试验表明，仅依帕列净和达格列净能显著改善葡萄糖耐量，这意味着胰岛素抵抗和分泌得到改善。综上所述，这些发现表明，尽管所有SGLT2抑制剂在2型糖尿病小鼠中均发挥抗糖尿病作用，但长效药物的这些药理作用可能略优，能够在一整天内提供良好的血糖控制。
