Choi Min-Koo, Nam So Jeong, Ji Hye-Young, Park Mi Jie, Choi Ji-Soo, Song Im-Sook
College of Pharmacy, Dankook University, Cheon-an 31116, Korea.
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea.
Pharmaceutics. 2020 Mar 15;12(3):268. doi: 10.3390/pharmaceutics12030268.
Since sodium-glucose cotransporter 2 (SGLT2) inhibitors reduced blood glucose level by inhibiting renal tubular glucose reabsorption mediated by SGLT2, we aimed to investigate the pharmacokinetics and kidney distribution of DWP16001, a novel SGLT2 inhibitor, and to compare these properties with those of dapagliflozin and ipragliflozin, representative SGLT2 inhibitors. The plasma exposure of DWP16001 was comparable with that of ipragliflozin but higher than that of dapagliflozin. DWP16001 showed the highest kidney distribution among three SGLT2 inhibitors when expressed as an area under curve (AUC) ratio of kidney to plasma (85.0 ± 16.1 for DWP16001, 64.6 ± 31.8 for dapagliflozin and 38.4 ± 5.3 for ipragliflozin). The organic anion transporter-mediated kidney uptake of DWP16001 could be partly attributed to the highest kidney uptake. Additionally, DWP16001 had the lowest half-maximal inhibitory concentration (IC) to SGLT2, a target transporter (0.8 ± 0.3 nM for DWP16001, 1.6 ± 0.3 nM for dapagliflozin, and 8.9 ± 1.7 nM for ipragliflozin). The inhibition mode of DWP16001 on SGLT2 was reversible and competitive, but the recovery of the SGLT2 inhibition after the removal of SGLT2 inhibitors in CHO cells overexpressing SGLT2 was retained with DWP16001, which is not the case with dapagliflozin and ipragliflozin. In conclusion, selective and competitive SGLT2 inhibition of DWP16001 could potentiate the efficacy of DWP16001 in coordination with the higher kidney distribution and retained SGLT2 inhibition of DWP16001 relative to dapagliflozin and ipragliflozin.
由于钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂通过抑制SGLT2介导的肾小管葡萄糖重吸收来降低血糖水平，我们旨在研究新型SGLT2抑制剂DWP16001的药代动力学和肾脏分布，并将这些特性与代表性SGLT2抑制剂达格列净和依帕列净的特性进行比较。DWP16001的血浆暴露量与依帕列净相当，但高于达格列净。当以肾脏与血浆的曲线下面积（AUC）比值表示时，DWP16001在三种SGLT2抑制剂中显示出最高的肾脏分布（DWP16001为85.0±16.1，达格列净为64.6±31.8，依帕列净为38.4±5.3）。有机阴离子转运体介导的DWP16001肾脏摄取可能部分归因于其最高的肾脏摄取。此外，DWP16001对靶转运体SGLT2的半数最大抑制浓度（IC）最低（DWP16001为0.8±0.3 nM，达格列净为1.6±0.3 nM，依帕列净为8.9±1.7 nM）。DWP16001对SGLT2的抑制模式是可逆和竞争性的，但在过表达SGLT2的CHO细胞中去除SGLT2抑制剂后，DWP16001仍保留SGLT2抑制作用的恢复，而达格列净和依帕列净则不然。总之，DWP16001对SGLT2的选择性和竞争性抑制作用，与更高的肾脏分布以及相对于达格列净和依帕列净而言DWP16001保留的SGLT2抑制作用协同，可能会增强DWP16001的疗效。
