二甲双胍遗传药理学研究进展

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(type2diabetes mellitus,T2DM)的一线药物,同时还可治疗多囊卵巢综合征(polycystic ovary syn-drome,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(organiccation transporters,OCTS)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OCTS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。     

二甲双胍的药物基因组学研究进展

近年来,有关2型糖尿病的诊疗指南不断更新,药物治疗策略日趋个体化。《中国2型糖尿病防治指南（2017版）》于2018年1月正式发布。新版指南进一步突出了二甲双胍在降糖治疗路径中的基石地位。然而,大量的临床研究结果表明：作为首选降糖药物,二甲双胍存在着显著的药物反应个体差异性。究其主因,学者多归转于遗传因素。相关研究绝大部分关注在药物靶蛋白、药物代谢酶、药物转运体蛋白的基因组学方面。因此,为丰富人们对二甲双胍药物反应个体差异性的认识,本文拟从药物基因组学的角度来综述二甲双胍的研究进展。     

浅谈降糖药二甲双胍的临床应用优势

糖尿病是一组以高血糖为特征的代谢性疾病,二甲双胍是治疗2型糖尿病的首选药物,而且是联合治疗糖尿病方案中的基础治疗药物,二甲双胍是目前全球应用较多的口服降糖药,文中首先分析了应用降糖药二甲双胍的必要性,进而分析二甲双胍的作用优势,旨在促进二甲双胍的临床应用。     

二甲双胍抗衰老临床研究与作用机制研究进展

二甲双胍是一种安全有效的糖尿病治疗药物,除具有降糖作用外,还具有保护心脏、抗炎和抗癌等作用.近年来,多项细胞和动物实验结果显示,二甲双胍具有抗衰老作用,一些临床试验结果也证明二甲双胍对年龄相关疾病具有积极作用,包括心血管疾病、癌症和神经退行性疾病等.该文对二甲双胍抗衰老相关的临床试验分子机制进行综述,探索二甲双胍在抗衰...     

二甲双胍联合Folfox6治疗结直肠癌合并2型糖尿病的临床疗效分析

目的观察二甲双胍联合Folfox6治疗结直肠癌合并2型糖尿病的临床效果和安全性。方法将2007年3月至2008年8月在我院肿瘤科住院治疗的50例2型糖尿病合并结直肠癌的患者随机分成两组,二甲双胍组接受二甲双胍联合Folfox6治疗,非二甲双胍组接受其他糖尿病药物联合Folfox6治疗。结果二甲双胍组治疗总有效率为60%,非二甲双胍组治疗总有效率为36%,差异有统计学意义(P<0.05);二甲双胍组腹泻与呕吐与非二甲双胍组相比,差异有统计学意义(P<0.05);二甲双胍组的5年生存率显著高于非二甲双胍组,差异有统计学意义(P<0.05)。结论二甲双胍联合Folfox6能显著提高2型糖尿病合并结直肠癌患者的临床疗效,值得在临床推广应用。     

Caco-2细胞中二甲双胍的摄取和转运特征

目的从细胞和分子水平考察二甲双胍在Caco-2细胞上的摄取和通透性质,探讨二甲双胍与药物抵抗蛋白特别是P-gp的相互关系。方法HPLC方法对二甲双胍在Caco-2细胞摄取和通透性作定量分析;RT-PCR方法测定二甲双胍对MDR1基因表达的影响;钙黄绿素(calcein AM)测定体系考察二甲双胍与多药抗药性转运体(P-gp、MRP1和MRP2)的作用关系。结果二甲双胍在Caco-2细胞上摄取呈浓度相关性,且有较强通透性(Papp=2.86×10-6cm.s-1);二甲双胍摄取和转运不因P-gp特异性抑制剂维拉帕米存在与否而改变;二甲双胍能提高MDR1基因表达;对细胞中calcein水平无影响。结论二甲双胍在Caco-2细胞上易转运,不是P-gp底物,对MDR1表达有上调作用,对P-gp和MRPs无抑制作用。     

二甲双胍治疗骨关节炎的作用机制研究进展

骨关节炎是一种慢性退行性关节疾病,也是导致老年人慢性功能障碍的主要因素。二甲双胍是目前公认用于治疗糖尿病的一线药物,可能也对骨关节炎软骨具有保护作用。二甲双胍抑制软骨细胞炎症反应、调节软骨细胞代谢异常、影响软骨细胞分化。对二甲双胍治疗骨关节炎的作用机制做一综述,为二甲双胍临床应用提供参考。     

二甲双胍—老药新用

二甲双胍是一种常见口服降糖药物,有研究发现其可用来治疗多囊卵巢综合征、脂肪性肝炎以及艾滋病毒感染相关的代谢异常等疾病。新研究表明二甲双胍可降低糖尿病患者癌症的发病率和死亡率,随着人们对二甲双胍的抗肿瘤作用机制的深入研究,二甲双胍有望成为一种新型抗肿瘤药物。     

二甲双胍胃肠道不耐受的研究进展

二甲双胍是治疗2型糖尿病的一线用药,其最常见的药品不良反应是胃肠道反应,潜在的机制目前尚不清楚,且临床干预策略较少。二甲双胍与肠道的关系是研究的热点,近期研究表明胃肠道不耐受的机制可能与肠道因素相关。就肠道与二甲双胍不耐受性的最新研究进展进行综述,并概述治疗策略,为临床应用二甲双胍提供参考。     

二甲双胍治疗氯氮平所致脂质代谢紊乱的研究进展

氯氮平是治疗难治性精神分裂症最有效的非典型抗精神病药物,二甲双胍防治氯氮平所致脂质代谢紊乱的疗效和机制,目前已成为国内外该领域研究的热点问题。本文通过最新的相关研究,对二甲双胍治疗非典型抗精神病药物氯氮平所致脂质代谢紊乱的研究进展进行综述,为临床治疗提供参考。     

Multidrug and toxin extrusion protein 1-mediated interaction of metformin and Scutellariae radix in rats

1.?The metformin and Scutellariae radix extract (SB) combination has been previously reported to enhance anti-diabetic activity. Considering that organic cation transporters (OCTs) and multi-drug and toxin extrusion proteins (MATEs) in the liver and kidney are determinant factors on hepatic distribution and renal clearance of metformin, the effects of SB on OCT or MATE-mediated systemic exposure of metformin as well as on glucose tolerance and hypoglycemia were examined.

2.?Although SB inhibited metformin uptake through human transporters OCT1 and MATE1 in vitro, the systemic exposures of metformin in vivo rats were not altered after metformin treatment with and without SB due to unchanged renal excretion of metformin.

3.?However, 28-day metformin treatment with SB decreased the mRNA level of hepatic MATE1 in rats, resulting in reduced biliary excretion of metformin and thereby higher concentration of metformin in the liver. In addition, in rats with 28-day metformin treatment with SB, glucose tolerance and plasma lactate level were enhanced, while hypoglycemia was not detected.

4.?Thus in rats, intervention of SB on transporter-mediated metformin transportation partially improves glucose tolerance without hypoglycemia and increases hepatic distribution of metformin. Also the further investigations in humans are required to clarify the relevance of these findings to the clinical significance.     

Prediction and validation of enzyme and transporter off-targets for metformin

Metformin, an established first-line treatment for patients with type 2 diabetes, has been associated with gastrointestinal (GI) adverse effects that limit its use. Histamine and serotonin have potent effects on the GI tract. The effects of metformin on histamine and serotonin uptake were evaluated in cell lines overexpressing several amine transporters (OCT1, OCT3 and SERT). Metformin inhibited histamine and serotonin uptake by OCT1, OCT3 and SERT in a dose-dependent manner, with OCT1-mediated amine uptake being most potently inhibited (IC₅₀ = 1.5 mM). A chemoinformatics-based method known as Similarity Ensemble Approach predicted diamine oxidase (DAO) as an additional intestinal target of metformin, with an E-value of 7.4 × 10^?5. Inhibition of DAO was experimentally validated using a spectrophotometric assay with putrescine as the substrate. The K_i of metformin for DAO was measured to be 8.6 ± 3.1 mM. In this study, we found that metformin inhibited intestinal amine transporters and DAO at concentrations that may be achieved in the intestine after therapeutic doses. Further studies are warranted to determine the relevance of these interactions to the adverse effects of metformin on the gastrointestinal tract.     

Effects of tetraalkylammonium compounds with different affinities for organic cation transporters on the pharmacokinetics of metformin

The study sought to investigate the effects of tetraalkylammonium (TAA), inhibitors of the organic cation transporters (OCTs) with different affinities, on the pharmacokinetics of metformin. The inhibitory potentials of TAAs on the uptake of metformin were evaluated by determining IC(50) values in MDCK cells over-expressing OCTs and, to assess in vivo drug interactions, metformin and TAAs were coadministered to rats. Uptake of metformin was facilitated by over-expression of hOCT1 and hOCT2 and showed saturable processes, indicating that metformin is a substrate of hOCT1 and hOCT2. The IC(50) values of TAAs for hOCT2 were lower than hOCT1 and decreased with increasing alkyl chain length, indicating that the inhibitory potential of TAAs on metformin uptake was greater in hOCT2 than in hOCT1 and increased with increasing alkyl chain length. The plasma concentration of metformin was elevated by the coadministration of tetrapropylammonium (TPrA) and tetrapentylammonium (TPeA), but not by tetramethylammonium (TMA) or tetraethylammonium (TEA). However, the plasma concentrations of TMA, TEA and TPrA were not changed by the coadministration of metformin. In conclusion, in vivo drug interactions between metformin and TAAs were caused only when metformin was coadministered with TAAs showing higher affinities for OCTs.     

Reduced Antidiabetic Effect of Metformin and Down-regulation of Hepatic Oct1 in Rats with Ethynylestradiol-Induced Cholestasis

Purpose  To investigate the effect of 17α-ethynylestradiol (EE)-induced cholestasis on the expression of organic cation transporters (Octs) in the liver and kidney, as well as the pharmacokinetics and pharmacodynamics of metformin in rats. Methods  Octs mRNA and protein expression were determined. The pharmacokinetics and tissue uptake clearance of metformin were determined following iv administration (5 mg/kg). Uptake of metformin, glucagon-mediated glucose production, and AMP-activated protein kinase (AMPK) activation were measured in isolated hepatocytes. The effect of metformin (30 mg/kg) on blood glucose levels was tested using the iv glucose tolerance test (IVGTT). Results  The mRNAs of hepatic Oct1, renal Oct1, and Oct2 were decreased by 71.1%, 37.6%, and 94.5%, respectively, by EE cholestasis. The hepatic Oct1 and renal Oct2 proteins were decreased by 30.6% and 60.2%, respectively. The systemic and renal clearance of metformin were decreased. The in vitro hepatocyte uptake of metformin was decreased by 86.4% for V _max. Suppression of glucagon-stimulated glucose production and stimulation of AMPK activation in hepatocytes by metformin were diminished. In addition, metformin did not demonstrate a glucose-lowering effect during IVGTT in EE cholestasis. Conclusion  The antidiabetic effect of metformin may be diminished in diabetic patients with EE cholestasis, due to impaired hepatic uptake of the drug via OCT1.     

Multiple Transport Mechanisms Involved in the Intestinal Absorption of Metformin: Impact on the Nonlinear Absorption Kinetics

The aim of this study was to investigate the contributions of multiple transport mechanisms to the intestinal absorption of metformin, focusing on OCT3, PMAT, THTR2, SERT and OCTN2. We also assessed the impact of these transporters on the nonlinear absorption of metformin. Uptake studies with MDCKII cells expressing OCT3, PMAT, THTR2 or SERT confirmed that metformin is a substrate of these transporters. Decynium22 strongly inhibited metformin uptake mediated by all the transporters. 7-Cyclopentyl inhibited OCT3- and THTR2-mediated uptake of metformin. AG835, thiamine and paroxetine specifically inhibited PMAT-, THTR2- and SERT-mediated uptake of metformin, respectively. Using these inhibitors, the relative contributions of OCT3, PMAT, THTR2, SERT, OCTN2 and others to the intestinal permeation of metformin across Caco-2 cells were estimated to be 9.77%, 9.68%, 22.2%, 1.52%, 0% and 0.66%, respectively. Concentration-dependent analysis of metformin uptake by Caco-2 cells revealed nonlinear kinetics with the similar K_m(app) value to the value for THTR2. Further in situ absorption study demonstrated that rat intestinal permeability of metformin was significantly decreased in the presence of decynium22, 7-cyclopentyl and thiamine. The present study indicated that THTR2 is the major determinant of the nonlinear absorption of metformin, although multiple transport mechanisms contribute to its intestinal absorption.     

Effect of high uric acid on the disposition of metformin: in vivo and in vitro studies

Metformin is always used as the baseline antidiabetic therapy for patients with type 2 diabetes mellitus (T2DM) and hyperuricemia. Metformin is excreted into urine through active secretion mediated by rOCTs and rMATE1.The aim of this study was to identify the effects of high uric acid on the disposition and its mechanism. For the in vivo study, a hyperuricemic animal model was induced by intraperitoneal injection of potassium oxonate (250 mg/kg) in rats. Metformin (100 mg/kg) was administered orally to investigate the pharmacokinetics in control and hyperuricemic rats, respectively. For the in vitro study, HEK293 and HepaRG cells were used to investigate the effect of uric acid (15 mg/dl) on the expression of OCT1, OCT2 and MATE1 and the disposition of metformin, respectively. The in vivo study showed that the AUC_0 → 600 of metformin was significantly decreased by 33.3%, whereas the cumulative urinary excretion of metformin was increased by 25.4% in hyperuricemic rats compared with that in control rats. The renal rOCT1, rOCT2 and rMATE1 and hepatic rMATE1 levels were increased in hyperuricemic rats compared with those in control rats, respectively. The in vitro study showed that uric acid could upregulate the expression of OCT2 and MATE1 in HEK293 cells and MATE1 in HepaRG cells and increase the intracellular metformin concentration in these two cell lines. These results demonstrated that a high uric acid level promoted urinary metformin excretion and decreased the plasma metformin concentration; the in vivo and in vitro studies provided a possible explanation being that high uric acid could upregulate the expression of renal metformin transporters OCTs and MATE1.     

Role of organic cation transporters in drug-induced toxicity

INTRODUCTION: Membrane transporters are important determinants of in vivo drug disposition, therapeutic efficacy and adverse drug reactions. Many commonly used drugs are organic cations and substrates of organic cation transporters (OCTs). These transporters have a large binding site containing partially overlapping interaction domains for different substrates and are specifically distributed around the body. Consequently, drug interactions with these transporters can result in specific toxicity. AREAS COVERED: This review describes the general properties of OCT and illustrates their importance for the development of important drug toxicities using the examples of metformin and cisplatin. Additionally, this review discusses the role of OCT polymorphisms in the modulation of these toxic effects. EXPERT OPINION: Understanding how drugs interact with membrane transporters is pivotally important in explaining the mechanisms of specific toxicities and also in designing new drugs or new therapeutic protective protocols by specific competition at the transporter. Defining the pharmacogenomics of these transporters will be essential to personalized medicine, enabling physicians to choose drugs for patients based on efficacy, availability, cost, safety, tolerability and convenience.     

药物转运体和代谢酶在抗生素药动学中的作用

近年来,对体内药物转运体的研究取得了重大进展,越来越多的转运体被发现及研究,其对药物的跨膜转运,具有重要的意义。各种转运体包括摄取转运体和外排转运体对药物的体内过程以及药物相互作用均有着重要影响。研究表明大多数抗生素的体内过程都与转运体和代谢酶有关,因此,归纳总结了转运体和代谢酶在抗生素的药动学和药物相互作用中的最新研究进展,为临床合理用药提供参考。     

Genetic variants of organic cation transporter 2 (OCT2) significantly reduce metformin uptake in oocytes

1.?The authors sought to evaluate the contribution of organic cation transporters (OCTs) to the renal tubular transport of metformin using LLC-PK1 cells as an in vitro model for the renal proximal tubule, and to investigate the effects of three non-synonymous genetic variants of OCT2 on the transport activity of metformin in vitro using an oocyte over-expression system.

2.?The basolateral-to-apical transport of metformin was significantly greater than the apical-to-basolateral transport and showed concentration dependency with the kinetic parameters: maximum transport rate (V_max), 922 pmol min^?1 per 5 × 10⁵ cells; Michaelis–Menten constant (K_m), 393 µM; intrinsic clearance (CL_int), 2.35 µl min^?1 per 5 × 10⁵ cells; and diffusion constant (K_d), 0.33 µl min^?1 per 5 × 10⁵ cells. The basolateral-to-apical transport of metformin was inhibited by phenoxybenzamine, an inhibitor of OCTs, but not by cyclosporine A, MK571, or fumitremorgin C, which are inhibitors of P-glycoprotein, multidrug resistance proteins (MRPs), and breast cancer resistance protein (BCRP), respectively, suggesting that OCTs play a role in renal tubular secretion of metformin.

3.?Metformin uptake was much greater in oocytes expressing OCT2-wild type (OCT2-WT) than OCT1-WT compared with uptake in water-injected oocytes. Uptake was significantly decreased in oocytes expressing OCT2-T199I, -T201M, and -A270S compared with that in OCT2-WT, suggesting that metformin is a better substrate for OCT2 than for OCT1 and that the amino acid-substituted variants of OCT2 cause a functional decrease in metformin uptake.

4.?In conclusion, the genetic variants of OCT2 (OCT2-T199I, -T201M, and -A270S) decreased the transport activity of metformin and thus may contribute to the inter-individual variation in metformin disposition as OCT2 plays a pivotal role in renal excretion, the major disposition route of metformin.