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《天津医科大学学报》[ISSN:1006-8147/CN:12-1259/R]

卷:

20卷

期数:

2014年03期

页码:

177-180

栏目:

基础医学

出版日期:

2014-05-20

文章信息/Info

Title:

Effect of methylene transformation between aromatic rings in dapagliflozin on pharmacokinetics and its active properties

文章编号:

1006-8147(2014)03-0177-04

作者:

 宋金芝¹; 2; 王玉丽²; 徐为人¹; 2; 赵桂龙²; 汤立达²

 （1.天津医科大学研究生院，天津 300070；2.天津药物研究院，天津市新药设计与发现重点实验室，天津 300193）

Author(s):

SONG Jin-zhi¹;  2; WANG Yu-li²; XU Wei-ren¹;  2; ZHAO Gui-long²; TANG Li-da²

（1.Graduate School, Tianjin Medical University, Tianjin 300070, China；2. Tianjin Institute of Pharmaceutical Research,Tianjin Key Laboratory of Molecular Design and Drug Discovery, Tianjin 300193, China）

关键词:

达格列净; 结构改造; 甲基取代; 活性; 药代参数

Keywords:

dapagliflozin ;  structural modification;  methyl substituted;  activity;  pharmacokinetic parameters

分类号:

-

DOI:

-

文献标志码:

A

摘要:

目的：考察达格列净芳环间亚甲基的取代对活性和药代性质的影响，为寻找更理想的药物探索改造的方向。方法：考察取代衍生物对正常大鼠糖负荷后的尿排糖量、血糖和尿量等指标，正常大鼠体内静脉给药和经口给药后的血药浓度，并计算药代参数。结果：(1)大鼠尿排糖和降血糖实验显示，与模型组相比，一甲基取代产物（TY702-5）和二甲基取代产物（TY702-5D）在0~6 h和6~24 h尿排糖量及0~3 h血糖抑制率呈剂量依赖性增加（P＜0.05）；同等剂量下，TY702-5和TY702-5D在0~6 h和6~24 h尿排糖量及0~3 h血糖抑制率明显低于达格列净组（P＜0.05）；同等剂量的TY702-5D的血糖抑制效果优于尿排糖效果。（2）体内吸收实验显示，与达格列净相比，TY702-5的吸收速度(Tmax)和程度(Cmax和AUC)增加，消除半衰期（T1/2）基本不变，组织分布和生物利用度下降。TY702-5D的药物吸收速度加快，吸收程度降低，组织分布增加，消除半衰期和生物利用度下降。结论：达格列净芳环间亚甲基改造后，药物的活性降低，且对尿糖和血糖的影响存在差异，对药物的各项药代参数有较大影响，提示利用这个位置结合其他部位进行改造，有可能得到一个更理想药物。

Abstract:

 Objective:To observe the effect on pharmacokinetics and active properties by transforming methylene between aromatic rings on dapagliflozin , and search for better drugs to explore the direction of transformation. Methods: Substituted derivatives were observed in normal rats about urine glucose excretion test, blood glucose and urine volume and other indicators, as well as the plasma concentration after intravenous administration and oral administration，based on which pharmacokinetic parameters were calculated. Results: (1)The urine glucose excretion and blood glucose test in rats displayed that compared with the model group, the urine glucose excretion during 0-6 h and 6-24 h and blood glucose inhibition rates during 0-3 h of one methyl-substituted product (TY702-5) group and dimethyl substituted product (TY702-5D) group were increased in at a dose-dependent rate(P<0.05); under the same dosage, the urine glucose excretion during 0-6 h and 6-24 h and blood sugar inhibition rates during 0-3 h of TY702-5 group and TY702-5D group were significantly lower than those of dapagliflozin group (P<0.05); under the same dosage, the blood sugar inhibition rates of TY702-5D group was better than the urine glucose excretion. (2)The absorption test in rats displayed that compared with dapagliflozin, the rate of absorption (Tmax) and extent (Cmax and AUC) for TY702-5were increased whereas elimination half-life (T1/2) maintained constant and tissue distribution and bioavailability were decreased. Furthermore, the rate of absorption and extent for TY702-5D were decreased and tissue distribution increased while elimination half-life and bioavailability were decreased. Conclusion: The methylene transformation between the aromatic ring of dapagliflozin can reduce the activity of the drug, and significant differences were found in its effects on urine glucose and blood glucose. And also has a greater impact on the pharmacokinetic parameters of the drug, indicating that a better drug can be acquired through the combination of this position and other parts of the transformation.

参考文献/References:

[1] Panchapakesan U，Pegg K，Gross S，et al．Effects of SGLT2 inhibition in human kidney proximal tubular cells—renoprotection in diabetic nephropathy?[J]．PLoS One，2013，8(2)：e54442
[2] Washburn W N，Poucher S M. Differentiating sodium-glucose co-transporter-2 inhibitors in development for the treatment of type 2 diabetes mellitus[J]．Expert Opin Investig Drugs，2013，22(4)：463
[3] Kipnes M．Dapagliflozin：an emerging treatment option in type 2 diabetes[J]．Expert Opin Investig Drugs，2009，18(3)：327
[4]Ferrannini E，Ramos S J，Salsali A，et al．Dapagliflozin monotherapy in type2diabetic patients with inadequate glycemic control by diet and exercise：a randomized，double-blind，placebo-controlled，phase3 trial[J]．Diabetes Care，2010，33（10）：2217
[5]Wilding J P，Norwood P，T’joen C，et al．A study of dapagliflozin in patients with type2 diabetes receiving high doses of insulin plus insulin sensitizers：applicability of a novel insulin-independent treatment[J]．Diabetes Care，2009，32（9）：1656

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　TENG Jie,CHEN Ye-gangTAO Wen-qi.Exploring the mechanism of protective effect of dapagliflozin or sacubitril/valsartan in rats with acute myocardial infarction[J].Journal of Tianjin Medical University,2023,29(03):406.

备注/Memo

备注/Memo:

基金项目 国家重大新药创制专项（2011ZX09401-009）；天津市科技支撑计划重点项目（10ZCKFSH01300）
作者简介 宋金芝（1987—），女，硕士在读，研究方向：降糖类新药药理研究；通信作者： 徐为人，E-mail: xuwr@tjipr.com。

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更新日期/Last Update: 2014-05-12