二甲双胍遗传药理学研究进展

中国临床药理学与治疗学 ›› 2011, Vol. 16 ›› Issue (11): 1315-1320.

• 综述与讲座 • 上一篇

二甲双胍遗传药理学研究进展

董敏, 刘昭前

中南大学临床药理研究所,湖南省遗传药理学重点实验室,长沙 410078,湖南

收稿日期:2011-08-05 修回日期:2011-10-03 出版日期:2011-11-26 发布日期:2011-11-29
通讯作者: 刘昭前, 通信作者, 男,博士,教授,博士生导师,研究方向:遗传药理学和临床药理学。Tel: 0731-84805380 E-mail: liuzhaoqian63@126.com
作者简介:董敏,女,博士,研究方向:遗传药理学与药物基因组学。Tel: 0731-84805380 E-mail: dongminhope@sina.com
基金资助:
国家高技术研究发展计划(863计划)(2009AA022704);国家自然科学基金项目(30873089,81173129);教育部“长江学者”创新团队 (IRT-0946),湖南省高校创新平台开放基金(10K078);湖南省科技计划重点项目(2009TP4068-2);中央高校基本科研业务费专项资金(201023100001)

Progress of the pharmacokinetics of metformin in type 2 diabetes mellitus

DONG Min, LIU Zhao-qian

Institute of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, Central South University Xiangya School of Medicine, Changsha 410078, Hunan, China

Received:2011-08-05 Revised:2011-10-03 Online:2011-11-26 Published:2011-11-29

摘要/Abstract

摘要： 遗传药理学研究发现药物代谢酶、受体和转运体基因遗传多态性是药物作用个体差异的重要决定因素。二甲双胍是治疗2型糖尿病(type 2 diabetes mellitus, T2DM)的一线药物,同时还可治疗多囊卵巢综合征(polycystic ovary syndrome, PCOS)等其他与胰岛素抵抗有关的疾病。二甲双胍在临床使用中表现出显著的药物反应个体差异,这种差异性导致药物反应性降低或药物毒副反应的发生。有机阳离子转运体(organic cation transporters, OCT_S)遗传多态性对二甲双胍药物反应个体差异有重要影响。本文阐述了OCT_S等多个药物相关基因的遗传多态性对二甲双胍药代动力学和药效学的影响,可为临床制定二甲双胍的个体化用药提供参考。

关键词: 二甲双胍, 2型糖尿病, 遗传药理学, 有机阳离子转运体, 药物反应性

Abstract: Pharmacogenetics indicates that genetic polymorphisms of drug metabolizing enzymes, receptors, and transporter are the major causes for individual difference in drug response. Metformin is regarded as insulin sensitizing drugs and the first-line agent for type 2 diabetes mellitus (T2DM) patients with overweight or obesity. Metformin is also used for treatment polycystic ovary syndrome (PCO_S). Considerable individual differences in metformin efficacy are reported. Organic cation transporters (OCT_S) play the important roles in the individual difference of metformin response rather than drug metabolizing enzymes and drug receptors. Thus we reviews the effects of the polymorphisms of OCT_S on metformin response and the progress of the pharmacokinetics of metformin in T2DM.

Key words: Metformin, Pharmacogenetics, OCT_S, Metformin response, Genetic polymorphisms

中图分类号:

R968

董敏, 刘昭前. 二甲双胍遗传药理学研究进展[J]. 中国临床药理学与治疗学, 2011, 16(11): 1315-1320.

DONG Min, LIU Zhao-qian. Progress of the pharmacokinetics of metformin in type 2 diabetes mellitus[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2011, 16(11): 1315-1320.

参考文献

[1] Wild S, Roglic G, Green A, et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030[J]. Diabetes Care, 2004, 27(10): 1047-1053.
[2] Bailey CJ, Turner RC. Metformin[J]. N Engl J Med, 1996, 334(9): 574-579.
[3] Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update[J]. Ann Intern Med, 2002, 137(1): 25-33.
[4] Diamanti-Kandarakis E, Kouli C, Tsianateli T, et al. Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome[J]. Eur J Endocrinol, 138(3): 269-274.
[5] Stumvoll M, Nurjhan N, Perriello G, et al. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus[J]. N Engl J Med, 1995, 333(9): 550-554.
[6] Dominguez LJ, Davidoff AJ, Srinivas PR, et al. Effects of metformin on tyrosine kinase activity, glucose transport, and intracellular calcium in rat vascular smooth muscle[J]. Endocrinology, 1996, 137(1): 113-121.
[7] Matthaei S, Hamann A, Klein HH, et al. Association of metformin's effect to increase insulin- stimulated glucose transport with potentiation of insulin-induced translocation of glucose transporters from intracellular pool to plasma membrane in rat adipocytes[J]. Diabetes, 1991, 40(7): 850-857.
[8] Hundal HS, Ramlal T, Reyes R, et al. Cellular mechanism of metformin action involves glucose transporter translocation from an intracellular pool to the plasma membrane in L6 muscle cells[J]. Endocrinology, 1992, 131(3): 1165-1173.
[9] Sambol NC, Chiang J. Pharmacokinetics and pharmacodynamics of metformin on healthy subjects with noninsulin-dependent diabetes mellitus[J]. J Clin Pharmacol, 1996, 36(11): 1012-1021.
[10] Kimura N, Masuda S, Tanihara Y, et al. Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1[J]. Drug Metab Pharmacokinet, 2005, 20(5): 379-386.
[11] Dresser MJ, Xiao G, Leabman MK, et al. Interactions of N-tetraalkylammonium compounds and biguanides with a human renal organic cation transporter (hOCT2)[J]. Pharm Res, 2002, 19(8): 1244- 1247.
[12] Cascorbi I. Pharmacogenetics of cytochrome P4502D6: genetic background and clinical implication [J]. Eur J Clin Invest, 2003, 33(12): 17-22.
[13] Campbell IW. Management of type 2 diabetes mellitus with special reference to metformin therapy [J]. Diabetes Metab, 1991, 17(1/2): 191-196.
[14] Turner RC, Cull CA, Frighi V, et al. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49)[J]. JAMA, 1999, 281(121): 2005-2012.
[15] Ieiri I, Takane H, Hirota T, et al. Genetic polymorphisms of drug transporters: pharmacokinetic and pharmacodynamic consequences in pharmacotherapy[J]. Expert Opin Drug Metab Toxicol, 2006, 2(5): 651-674.
[16] Sogame Y, Kitamura A, Yabuki M, et al. A comparison of uptake of metformin and phenformin mediated by hOCT1 in human hepatocytes[J]. Biopharm Drug Dispos, 2009, 30(8): 476-484.
[17] Izzedine H, Launay-Vacher V, Deray G. Renal tubular transporters and antiviral drugs: an update[J]. AIDS, 2005, 19(5): 455-462.
[18] Fukushima-Uesaka H, Maekawa K, Ozawa S, et al. Fourteen novel single nucleotide polymorphisms in the SLC22A2 gene encoding human organic cation transporter (OCT2)[J]. Drug Metab Pharmaco- kinet, 2004, 19(3): 239-244.
[19] Nies AT, Koepsell H, Winter S, et al. Expression of organic cation trans-porters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by geneticfactors and cholestasis in human liver[J]. Hepatology, 2009, 50(4): 1227-1240.
[20] Koepsell H, Endou H. The SLC22 drug transporter family[J]. Eur J Physiol, 2004, 447(5): 666-676.
[21] Shu Y, Leabman MK, Feng B, et al. Evolutionary conservation predicts function of variants of the human organic cation transporter, OCT1[J]. Proc Natl Acad Sci USA, 2003, 100(10): 5902-5907.
[22] Shu Y, Brown C, Castro RA, et al. Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics[J]. Clin Pharmacol Ther, 2007, 83(2): 273-280.
[23] Shu Y, Sheardown SA, Brown C, et al. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action[J]. J Clin Invest, 2007, 117(5): 1422-1431.
[24] Sakata T, Anzai N, Shin HJ, et al. Novel single nucleotide polymorphisms of organic cation transporter 1 (SLC22A1) affecting transport functions[J]. Biochem Biophys Res Commun, 2004, 313(3): 789-793.
[25] Takane H, Shikata E, Otsubo K, et al. Polymorphism in human organic cation transporters and metformin action[J]. Pharmacogenomics, 2008, 9(4): 415-422.
[26] Itoda M, Saito Y, Maekawa K, et al. Seven novel single nucleotide polymorphisms in the human SLC22A1 gene encoding organic cation transporter 1 (OCT1)[J]. Drug Metab Pharmacokine, 2004, 19(4): 308-312.
[27] Chen Y, Li S, Brown C, et al. Effect of genetic variation in the organic cation transporter 2 on the renal elimination of metformin[J]. Pharmacogenet Genomics, 2009, 19(4): 497-504.
[28] Zolk O, Solbach TF, Konig J, et al. Structural determinants of inhibitorinteraction with the human organic cation transporter OCT2 (SLC22A2)[J]. Naunyn Schmiedebergs Arch Pharmacol, 2009, 379(4): 337-348.
[29] Leabman MK, Giacomini KM. Estimating the contribution of genes and environment to variation in renal drug clearance[J]. Pharmacogenetics, 2003, 13(9): 581-584.
[30] Song I, Shin H, Shim E, et al. Genetic variants of the organic cation transporter 2 influence the disposition of metformin[J]. Clin Pharmacol Ther, 2008, 84(5): 559-562.
[31] Wang Z, Yin O, Chow M. OCT2 polymorphism in vivo renal functional consequence: studies with metformin and cimetidine[J]. Clin Pharmacol Ther, 2007, 18(7): 637-645.
[32] Legro RS, Barnhart HX, Schlaff WD, et al. Ovulatory Response to treatment of polycystic ovary syndrome is associated with a polymorphism in the STK11 gene[J]. J Clin Endocrinol Metab Doi, 2008, 93(3): 792-800.
[33] Ertunc D, Tok EC, Aktas A, et al. The importance of IRS-1 Gly972Arg polymorphism in evaluating the response to metformin treatment in polycystic ovary syndrome[J]. Hum Reprod, 2005, 20(5): 1207-1212.

二甲双胍遗传药理学研究进展

Progress of the pharmacokinetics of metformin in type 2 diabetes mellitus

PDF (PC)

可视化

被引次数

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价

[1]	马言, 田高鹏, 石兴文, 孙婷, 谢晶晶, 甄东户. 探讨T2DM人群中25（OH）D与代谢相关性脂肪肝的相关性[J]. 中国临床药理学与治疗学, 2023, 28(9): 1018-1026.
[2]	马仙康, 杨丽霞, 崔阳阳, 米登海. 当归多糖通过抑制GRP78、p-PERK、p-Eif2α表达改善糖尿病KK-Ay小鼠肝内质网应激[J]. 中国临床药理学与治疗学, 2023, 28(8): 926-936.
[3]	侯瑞英, 郭莉阁, 焦伟杰, 杜蕾, 吴桂月, 赵旭. 消渴舒方对2型糖尿病模型大鼠血清炎症因子的影响及其机制研究[J]. 中国临床药理学与治疗学, 2023, 28(4): 377-382.
[4]	赵世峰, 宋向明, 姚建平. 新型胰高血糖素样肽-1受体/葡萄糖依赖性促胰岛素多肽受体双重激动剂——Tirzepatide[J]. 中国临床药理学与治疗学, 2023, 28(2): 220-227.
[5]	王洁, 李龙, 陈凤, 刘胜菲. 二甲双胍干预肺纤维化发病机制的研究进展[J]. 中国临床药理学与治疗学, 2023, 28(2): 235-240.
[6]	杜小雨, 李宇蒙, 吴惠珍, 邱博. 多格列艾汀治疗2型糖尿病的药理作用和临床评价[J]. 中国临床药理学与治疗学, 2023, 28(10): 1177-1183.
[7]	蔡静, 潘斌晶, 刘靖芳. 降糖药物与肌肉减少症关系的研究进展[J]. 中国临床药理学与治疗学, 2023, 28(1): 101-108.
[8]	王歆, 刘维英, 武晨, 开锦军, 梁雪杰, 常瑛璇. 二甲双胍调节AMPK/SREBP-1通路及在临床中的应用进展[J]. 中国临床药理学与治疗学, 2022, 27(9): 1049-1054.
[9]	翟葳葳, 余巧玲, 刘平, 邱博, 吴惠珍. 非奈利酮在2型糖尿病合并慢性肾病治疗中的研究进展[J]. 中国临床药理学与治疗学, 2022, 27(9): 1067-1074.
[10]	卢森林, 刘欣元, 王吉莉, 黄晓飞. 病毒载体介导的基因治疗在2型糖尿病中的研究进展[J]. 中国临床药理学与治疗学, 2022, 27(7): 800-807.
[11]	王珍, 全海燕, 洪陈亮, 袁李佳龙, 秦旭平. 游泳运动通过促进自噬改善糖尿病小鼠肾功能的研究[J]. 中国临床药理学与治疗学, 2022, 27(6): 632-638.
[12]	曾晓凡, 许宜琪, 刘书, 吴茜, 李自保, 何俊俊, 金岳龙, 赵永莉, 何春玲, 高家林. 回顾性分析小剂量阿司匹林对2型糖尿病病人非致死性心梗和脑梗一级预防的作用[J]. 中国临床药理学与治疗学, 2022, 27(6): 665-671.
[13]	邵茜, 郁亚南, 黄钰涵, 王晓彤, 凌宏威, 吕冬梅, 王涛. 艾塞那肽降低2型糖尿病患者体重的预测因素研究[J]. 中国临床药理学与治疗学, 2022, 27(3): 287-294.
[14]	陈佳音, 王丽, 王立军, 童刚领, 马洁, 陈西敬, 卢杨. 有机阳离子转运体基因多态性与奥沙利铂毒性及疗效的相关性研究[J]. 中国临床药理学与治疗学, 2022, 27(2): 171-177.
[15]	代红雨, 杨坤, 胡如春, 周红梅, 马佩敏, 郝倩. 0.25%罗哌卡因用于糖尿病患者坐骨神经阻滞的时效研究[J]. 中国临床药理学与治疗学, 2022, 27(11): 1278-1284.