Dapagliflozin, a Novel SGLT2 Inhibitor, Induces Dose-Dependent Glucosuria in Healthy Subjects
Dapagliflozin, a Novel SGLT2 Inhibitor, Induces Dose-Dependent Glucosuria in Healthy Subjects
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DOI：
10.1038/clpt.2008.251
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发表时间：
2009-05-01
影响因子：
6.7
通讯作者：
Pfister, M.
中科院分区：
文献类型：
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作者：
Komoroski, B.;Vachharajani, N.;Pfister, M.
达帕利嗪通过抑制钠-葡萄糖共转运体-2(SGLT2)选择性地抑制肾葡萄糖重吸收。它是作为一种治疗2型糖尿病(T2 DM)的胰岛素非依赖性治疗方法而发展起来的。在健康受试者中进行单次递增剂量(SAD；2.5-500 mg)和多个递增剂量(MAD；每天2.5-100 mg，连续14天)研究，评价药物的安全性、耐受性、药代动力学和药效学。达帕利嗪的血药浓度呈剂量比例关系，半衰期约为17h。血糖尿量也呈剂量依赖性。第1天的累积葡萄糖排泄量与2.5-100毫克(MAD)的剂量有关，范围为18至62克；第14天的数值与第1天的数值相当，血糖参数没有明显变化。类似剂量的20-50毫克对SGLT2的抑制作用接近最大值，至少持续24小时。达格列酮表现出药代动力学(PK)特征和持续超过24小时的剂量依赖性血糖，这表明它适合每天一次给药，并表明有必要对其在T2 DM患者中的疗效进行进一步研究。
Dapagliflozin selectively inhibits renal glucose reabsorption by inhibiting sodium-glucose cotransporter-2 (SGLT2). It was developed as an insulin-independent treatment approach for type 2 diabetes mellitus (T2DM). The safety, tolerability, pharmacokinetics, and pharmacodynamics of the drug were evaluated in single-ascending- dose (SAD; 2.5-500 mg) and multiple-ascending-dose (MAD; 2.5-100 mg daily for 14 days) studies in healthy subjects. Dapagliflozin exhibited dose-proportional plasma concentrations with a half-life of similar to 17 h. The amount of glucosuria was also dose-dependent. Cumulative amounts of glucose excreted on day 1, relating to doses from 2.5-100 mg (MAD), ranged from 18 to 62 g; day 14 values were comparable to day 1 values, with no apparent changes in glycemic parameters. Doses of similar to 20-50 mg provided close-to-maximal SGLT2 inhibition for at least 24 h. Dapagliflozin demonstrates pharmacokinetic (PK) characteristics and dose-dependent glucosuria that are sustained over 24 h, which indicates that it is suitable for administration in once-daily doses and suggests that further investigation of its efficacy in T2DM patients is warranted.