药学学报, 2017, 52(6): 865-870
引用本文:
许希宁, 石荣, 马越鸣. 基于药物转运体机制的二甲双胍体内过程研究进展[J]. 药学学报, 2017, 52(6): 865-870.
XU Xi-ning, SHI Rong, MA Yue-ming. Research progress of pharmacokinetics of metformin based on transporters[J]. Acta Pharmaceutica Sinica, 2017, 52(6): 865-870.

基于药物转运体机制的二甲双胍体内过程研究进展
许希宁, 石荣, 马越鸣
上海中医药大学中药学院, 上海 201203
摘要:
转运体在药物的吸收、分布以及排泄过程中发挥着重要作用。明确药物转运机制有利于提高药物安全性和有效性,从而指导临床合理用药。二甲双胍作为2型糖尿病的临床一线用药,多种转运体参与了其体内过程,转运体表达和功能的改变直接影响其药动学和药效学。本文综述了基于药物转运体机制的二甲双胍体内过程,这些转运体包括有机阳离子转运体(OCTs)、多药及毒性化合物外排转运蛋白(MATE)、质膜单胺蛋白转运体(PMAT)、五羟色胺转运体(SERT)、硫胺素转运体2(THTR-2)、肉碱/有机阳离子体1(OCTN1)。
关键词:    转运体      二甲双胍      药动学      药物-药物相互作用      有机阳离子转运体      多药及毒性化合物外排转运蛋白     
Research progress of pharmacokinetics of metformin based on transporters
XU Xi-ning, SHI Rong, MA Yue-ming
College of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
Abstract:
Drug transporters play vital roles in absorption, distribution and excretion of drugs. Under­standing the transport activity can improve the effectiveness and safety of drugs and guide clinical rational use of drugs. Metformin is a first-line drug in the treatment of type 2 diabetes mellitus, of which the pharmacokinetics involves several transporters. The changes in expression and function of these transporters affect directly the pharmacokinetics/pharmacodynamics of metformin. This paper reviews the research progress of pharmacokinetics of metformin based on transporters, and these transporters are organic cation transporters (OCTs), multidrug and toxin extrusion proteins (MATE), plasma membrane monoamine transporter protein (PMAT), serotonin reuptake transporter (SERT), thiamine transporter 2 (THTR-2), and carnitine/organic cation 1 (OCTN1).
Key words:    transporter    metformin    pharmacokinetics    drug-drug interaction    organic cation transporter    multidrug and toxin extrusion protein   
收稿日期: 2016-11-29
DOI: 10.16438/j.0513-4870.2016-1148
基金项目: 国家自然科学基金资助项目(81303296);杏林学者(2013)
通讯作者: 石荣,TEL/Fax:86-21-51322386,E-mail:rongshi56@126.com
Email: rongshi56@126.com
相关功能
PDF(298KB) Free
打印本文
0
作者相关文章
许希宁  在本刊中的所有文章
石荣  在本刊中的所有文章
马越鸣  在本刊中的所有文章

参考文献:
[1] Mu YM, Ji LN, Ni G, et al. Expert consensus on clinical application of metformin [J]. Chin J Diabetes (中国糖尿病杂志), 2014, 22: 673-681.
[2] Zhong HW, LANG JM, Ye JH, et al. Effects of metformin on insulin resistance and leptin levels in patients with metabolic syndrome [J]. Chin Med Her (中国医药导报), 2011, 8: 80-81.
[3] UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complica­tions in overweight patients with type 2 diabetes (UKPDS 34) [J]. Lancet, 1998, 352: 854-865.
[4] Garber AJ, Abrahamson MJ, Barzilay JI,et al. American Association of Clinical Endocrinologists' comprehensive diabetes management algorithm 2013 consensus statement-executive summary [J]. Endocr Pract, 2013, 19: 536-557.
[5] Yu Q. Expert consensus on diagnosis and treatment of polycystic ovary syndrome [J]. Chin J Pract Gynecol Obstetr (中国实用妇科与产科杂志), 2007, 23: 474.
[6] Barbero-Becerra VJ, Santiago-Hernandez JJ, Villegas-Lopez FA,et al. Mechanisms involved in the protective effects of metformin against nonalcoholic fatty liver disease [J]. Curr Med Chem, 2012, 19: 2918-2923.
[7] XUE Chao-jun LK-x. Advances of the anti-tumor research of metformin [J]. Acta Pharm Sin (药学学报), 2015, 50: 1210-1216.
[8] Qi H, Liu TT, Li GR. Effect and mechanism of metformin on prolonging life span [J]. Chin J Clin Pharm Ther (中国临床药理学与治疗学), 2012, 17: 1295-1301.
[9] Audia P, Feinfeld DA, Dubrow A,et al. Metformin-induced lactic acidosis and acute pancreatitis precipitated by diuretic, celecoxib, and candesartan-associated acute kidney dysfunction [J]. Clin Toxicol (Phila), 2008, 46: 164-166.
[10] Tucker GT, Casey C, Phillips PJ,et al. Metformin kinetics in healthy subjects and in patients with diabetes mellitus [J]. Br J Clin Pharmacol, 1981, 12: 235-246.
[11] Zamek-Gliszczynski MJ, Bao JQ, Day JS,et al. Metformin sinusoidal efflux from the liver is consistent with negligible biliary excretion and absence of enterohepatic cycling [J]. Drug Metab Dispos, 2013, 41: 1967-1971.
[12] Nies AT, Herrmann E, Brom M, et al. Vectorial transport of the plant alkaloid berberine by double-transfected cells expressing the human organic cation transporter 1 (OCT1, SLC22A1) and the efflux pump MDR1 P-glycoprotein (ABCB1) [J]. Naunyn Schmiedebergs Arch Pharmacol, 2008, 376: 449-461.
[13] Graham DGG, Punt J, Arora M, et al. Clinical pharmacoki­netics of metformin [J]. Clin Pharmacokinet, 2011, 2: 81-98.
[14] Markovic TP, Jenkins AB, Campbell LV, et al. The determi­nants of glycemic responses to diet restriction and weight loss in obesity and NIDDM [J]. Diabetes Care, 1998, 21: 687-694.
[15] Ito N, Ito K, Ikebuchi Y, et al. Organic cation transporter/solute carrier family 22a is involved in drug transfer into milk in mice [J]. J Pharm Sci, 2014, 103: 3342-3348.
[16] Choi MK, Song IS. Organic cation transporters and their pharmacokinetic and pharmacodynamic consequences [J]. Drug Metab Pharmacokinet, 2008, 23: 243-253.
[17] Muller J, Lips KS, Metzner L, et al. Drug specificity and intestinal membrane localization of human organic cation transporters (OCT) [J]. Biochem Pharmacol, 2005, 70: 1851-1860.
[18] Han TK, Everett RS, Proctor WR, et al. Organic cation transporter 1 (OCT1/mOct1) is localized in the apical mem­brane of Caco-2 cell monolayers and enterocytes [J]. Mol Pharmacol, 2013, 84: 182-189.
[19] Jensen JB, Sundelin EI, Jakobsen S, et al. [11C]-Labeled metformin distribution in the liver and small intestine using dynamic positron emission tomography in mice demonstrates tissue-specific transporter dependency [J]. Diabetes, 2016, 65: 1724-1730.
[20] Shirasaka Y, Lee N, Zha W, et al. Involvement of organic cation transporter 3 (Oct3/Slc22a3) in the bioavailability and pharmacokinetics of antidiabetic metformin in mice [J]. Drug Metab Pharmacokinet, 2016, 31: 385-388.
[21] 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: 476-484.
[22] Wang DS, Jonker JW, Kato Y, et al. Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin [J]. J Pharmacol Exp Ther, 2002, 302: 510-515.
[23] Bachmakov I, Glaeser H, Fromm MF, et al. Interaction of oral antidiabetic drugs with hepatic uptake transporters: focus on organic anion transporting polypeptides and organic cation transporter 1 [J]. Diabetes, 2008, 57: 1463-1469.
[24] Kimura N, Okuda M, Inui K. Metformin transport by renal basolateral organic cation transporter hOCT2 [J]. Pharm Res, 2005, 22: 255-259.
[25] Tzvetkov MV, Vormfelde SV, Balen D, et al. The effects of genetic polymorphisms in the organic cation transporters OCT1, OCT2, and OCT3 on the renal clearance of metformin [J]. Clin Pharmacol Ther, 2009, 86: 299-306.
[26] Ding Y, Jia Y, Song Y, et al. The effect of lansoprazole, an OCT inhibitor, on metformin pharmacokinetics in healthy subjects [J]. Eur J Clin Pharmacol, 2014, 70: 141-146.
[27] Umamaheswaran G, Praveen RG, Damodaran SE, et al. Influence of SLC22A1 rs622342 genetic polymorphism on metformin response in South Indian type 2 diabetes mellitus patients [J]. Clin Exp Med, 2015, 15: 511-517.
[28] Tarasova L, Kalnina I, Geldnere K, et al. Association of genetic variation in the organic cation transporters OCT1, OCT2 and multidrug and toxin extrusion 1 transporter protein genes with the gastrointestinal side effects and lower BMI in metformin-treated type 2 diabetes patients [J]. Pharmacogenet Genomics, 2012, 22: 659-666.
[29] Gambineri A, Tomassoni F, Gasparini DI, et al. Organic cation transporter 1 polymorphisms predict the metabolic response to metformin in women with the polycystic ovary syndrome [J]. J Clin Endocrinol Metab, 2010, 95: E204-208.
[30] Joerger M, van Schaik RH, Becker ML, et al. Multidrug and toxin extrusion 1 and human organic cation transporter 1 polymorphisms in patients with castration-resistant prostate cancer receiving metformin (SAKK 08/09) [J]. Prostate Cancer Prostatic Dis, 2015, 18: 167-172.
[31] Duan R, Pak C, Jin P. Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA [J]. Hum Mol Genet, 2007, 16: 1124-1131.
[32] Wang ZJ, Yin OQ, Tomlinson B, et al. OCT2 polymorphisms and in-vivo renal functional consequence: studies with metformin and cimetidine [J]. Pharmacogenet Genomics, 2008, 18: 637-645.
[33] Yoon H, Cho HY, Yoo HD, et al. Influences of organic cation transporter polymorphisms on the population pharmacokinetics of metformin in healthy subjects [J]. AAPS J, 2013, 15: 571-580.
[34] Hou W, Zhang D, Lu W, et al. Polymorphism of organic cation transporter 2 improves glucose-lowering effect of metformin via influencing its pharmacokinetics in Chinese type 2 diabetic patients [J]. Mol Diagn Ther, 2015, 19: 25-33.
[35] Song IS, Shin HJ, Shin JG. Genetic variants of organic cation transporter 2 (OCT2) significantly reduce metformin uptake in oocytes [J]. Xenobiotica, 2008, 38: 1252-1262.
[36] Chen L, Pawlikowski B, Schlessinger A, et al. Role of organic cation transporter 3 (SLC22A3) and its missense variants in the pharmacologic action of metformin [J]. Pharmacogenet Genomics, 2010, 20: 687-699.
[37] Pan X. Review of antidiabetic mechanism of metformin [J]. Chin J Diabetes (中国糖尿病杂志), 2016, 24: 665-668.
[38] YANG Yuan-yuan MY-m. Progress in the study of multidrug and toxin extrusion proteins [J]. Acta Pharm Sin (药学学报), 2014, 49: 1105-1110.
[39] Tanihara Y, Masuda S, Sato T, et al. Substrate specificity of MATE1 and MATE2-K, human multidrug and toxin extrusions/H+-organic cation antiporters [J]. Biochem Pharmacol, 2007, 74: 359-371.
[40] Otsuka M, Matsumoto T, Morimoto R, et al. A human transporter protein that mediates the final excretion step for toxic organic cations [J]. Proc Natl Acad Sci U S A, 2005, 102: 17923-17928.
[41] Ohta KY, Inoue K, Yasujima T, et al. Functional characteristics of two human MATE transporters: kinetics of cimetidine transport and profiles of inhibition by various compounds [J]. J Pharm Pharm Sci, 2009, 12: 388-396.
[42] Tsuda M, Terada T, Mizuno T, et al. Targeted disruption of the multidrug and toxin extrusion 1 (mate1) gene in mice reduces renal secretion of metformin [J]. Mol Pharmacol, 2009, 75: 1280-1286.
[43] Ma YR, Huang J, Shao YY, et al. Inhibitory effect of atenolol on urinary excretion of metformin via down-regulating multidrug and toxin extrusion protein 1 (rMate1) expression in the kidney of rats [J]. Eur J Pharm Sci, 2015, 68: 18-26.
[44] Grun B, Kiessling MK, Burhenne J, et al. Trimethoprim-metformin interaction and its genetic modulation by OCT2 and MATE1 transporters [J]. Br J Clin Pharmacol, 2013, 76: 787-796.
[45] Kusuhara H, Ito S, Kumagai Y, et al. Effects of a MATE protein inhibitor, pyrimethamine, on the renal elimination of metformin at oral microdose and at therapeutic dose in healthy subjects [J]. Clin Pharmacol Ther, 2011, 89: 837-844.
[46] Stocker SL, Morrissey KM, Yee SW, et al. The effect of novel promoter variants in MATE1 and MATE2 on the phar­macokinetics and pharmacodynamics of metformin [J]. Clin Pharmacol Ther, 2013, 93: 186-194.
[47] Christensen MM, Pedersen RS, Stage TB, et al. A gene-gene interaction between polymorphisms in the OCT2 and MATE1 genes influences the renal clearance of metformin [J]. Phar­macogenet Genomics, 2013, 23: 526-534.
[48] Wang J. The plasma membrane monoamine transporter (PMAT): Structure, function, and role in organic cation dispo­sition [J]. Clin Pharmacol Ther, 2016, 100:489-499.
[49] Han TK, Proctor WR, Costales CL, et al. Four cation-selective transporters contribute to apical uptake and accumulation of metformin in Caco-2 cell monolayers [J]. J Pharmacol Exp Ther, 2015, 352: 519-528.
[50] Zhou M, Xia L, Wang J. Metformin transport by a newly cloned proton-stimulated organic cation transporter (plasma membrane monoamine transporter) expressed in human intes­tine [J]. Drug Metab Dispos, 2007, 35: 1956-1962.
[51] Barker EL, Kimmel HL, Blakely RD. Chimeric human and rat serotonin transporters reveal domains involved in recognition of transporter ligands [J]. Mol Pharmacol, 1994, 46: 799-807.
[52] Chen JX, Pan H, Rothman TP, et al. Guinea pig 5-HT trans­porter: cloning, expression, distribution, and function in intes­tinal sensory reception [J]. Am J Physiol, 1998, 275: G433-448.
[53] Seeman P, Madras BK. Anti-hyperactivity medication: meth­ylphenidate and amphetamine [J]. Mol Psychiatry, 1998, 3: 386-396.
[54] Yee SW, Lin L, Merski M, et al. Prediction and validation of enzyme and transporter off-targets for metformin [J]. J Pharmacokinet Pharmacodyn, 2015, 42: 463-475.
[55] Dujic T, Zhou K, Tavendale R, et al. Effect of serotonin transporter 5-HTTLPR polymorphism on gastrointestinal intolerance to metformin: a GoDARTS study [J]. Diabetes Care, 2016, 39: 1896-1901.
[56] Ganapathy V, Smith SB, Prasad PD. SLC19: the folate/thiamine transporter family [J]. Pflugers Arch, 2004, 447: 641-646.
[57] Nabokina SM, Subramanian VS, Valle JE, et al. Adaptive regulation of human intestinal thiamine uptake by extracellular substrate level: a role for THTR-2 transcriptional regulation [J]. Am J Physiol Gastrointest Liver Physiol, 2013, 305: G593-599.
[58] Liang X, Chien HC, Yee SW, et al. Metformin is a substrate and inhibitor of the human thiamine transporter, THTR-2 (SLC19A3) [J]. Mol Pharm, 2015, 12: 4301-4310.
[59] Amrein K, Ribitsch W, Otto R, et al. Severe lactic acidosis reversed by thiamine within 24 hours [J]. Crit Care, 2011, 15: 457.
[60] Tamai I, Yabuuchi H, Nezu J, et al. Cloning and characteri­zation of a novel human pH-dependent organic cation trans­porter, OCTN1 [J]. FEBS Lett, 1997, 419: 107-111.
[61] Nakamichi N, Shima H, Asano S, et al. Involvement of carnitine/organic cation transporter OCTN1/SLC22A4 in gas­trointestinal absorption of metformin [J]. J Pharm Sci, 2013, 102: 3407-3417.
[62] Futatsugi A, Masuo Y, Kawabata S, et al. L503F variant of carnitine/organic cation transporter 1 efficiently transports metformin and other biguanides [J]. J Pharm Pharmacol, 2016, 68: 1160-1169.
相关文献:
1.马彦荣, 武艳芳, 段颖琴, 张国强, 武新安.美托洛尔或/和普伐他汀对大鼠二甲双胍药动学的影响[J]. 药学学报, 2017,52(2): 253-257
2.王心怡, 张志荣.美吡拉敏敏感的、逆质子有机阳离子转运体的研究进展[J]. 药学学报, 2016,51(6): 886-891
3.翁娅韵, 金李莎, 汪宇清, 宋飞凤, 李丽萍, 周慧, 曾苏, 蒋惠娣.稳定表达人OCTN1/OCTN2的细胞模型构建及应用[J]. 药学学报, 2016,51(6): 931-937
4.雷红梅, 孙思源, 李丽萍, 涂美娟, 周慧, 曾苏, 蒋惠娣.稳定表达hMATE1及共表达hMATE1与hOCT1或hOCT2细胞模型的构建[J]. 药学学报, 2015,50(7): 842-847
5.杨媛媛, 马越鸣.多药及毒素外排转运蛋白研究进展[J]. 药学学报, 2014,49(8): 1105-1110
6.陈丽芳 焦建杰 张才丽 娄建石 刘昌孝.有限采样法估算口服盐酸二甲双胍的药动学参数[J]. 药学学报, 2010,45(12): 1533-1536
7.王芙蓉 郭瑞臣.新型有机阳离子转运体-2调控研究进展[J]. 药学学报, 2009,44(10): 1061-1065