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。     

药物转运体与药物体内过程

关于药物在机体内的跨膜转运机制,以往的研究多侧重于药物理化性质.近年,发现体内存在多种转运蛋白(转运体)系统,对药物体内跨膜转运,有重要意义,有时甚至起决定性作用,因此,药物转运体对药物的体内过程,即药物的吸收、分布、代谢和排泄及药物之间的相互作用有重要影响,并可影响或决定药物的动力学过程.     

有机阴离子转运多肽介导的药物相互作用研究进展

药物转运体介导的药物相互作用正日益受到人们的关注和重视,近年来的研究表明药物转运体对药物的吸收、分布和排出有着重要的作用。有机阴离子转运多肽是一类药物摄取转运体,其表达分布广泛,转运的内源性和外源性的底物众多,一些药物因抑制有机阴离子转运体而导致药物相互作用。本文综述了有机阴离子转运多肽家族不同成员的组织分布、结构特点以及其介导的药物相互作用的最新研究进展。     

药物转运体OAT2研究进展

有机阴离子转运体2(OAT2)属于有机阴离子转运体家族成员,主要分布于肝肾,介导肌酐、尿酸等内源性物质及多种外源性药物的跨膜转运。OAT2对外源性物质如药物的体内过程如吸收、分布、代谢和排泄过程起着重要作用。研究表明OAT2的表达与活性被药物、疾病、性别及基因多态性等多种因素影响,亦受到核受体等信号通路调控。故本文综述药物转运体OAT2的结构与分布、底物、调控机制、临床意义的研究进展,为OAT2可能介导药物相互作用及药物疗效预测提供参考。     

药物转运体与中枢神经药理

细胞膜上有三类主要的功能蛋白，即膜受体、离子通道与转运体。转运体是细胞内外物质转运的分子基础，包括离子转运体、神经递质转运体、营养物质（如氨基酸、葡萄糖等）转运体以及外来物质转运体。药物转运体（drug transporter）本质上属于外来物质（xenobiotic）转运体，是机体内物质转运系统的组成部分。药物转运体在药物吸收、分布、代谢、排泄等体内过程中起非常重要的作用，是影响药物效应以及产生药物相互作用的重要因素。近年来，对药物转运体的了解逐步深入，成为药理学研究中不可忽视的一个组成部分。     

肾脏转运体和/或代谢酶介导药物排泄及药物相互作用的研究进展

肾脏是人体最重要的排泄器官。肾单元近端小管细胞具有多种药物转运体和代谢酶,在药物及其代谢物处置中发挥关键作用。近端小管细胞中主要转运体包括有机阴离子转运体、有机阳离子转运体、有机阳离子/肉毒碱转运体、多药及毒素外排转运蛋白、P-糖蛋白、乳腺癌耐药蛋白和多药耐药相关蛋白;主要代谢酶包括细胞色素P450酶,UDP-葡萄糖醛酸基转移酶、磺酸基转移酶、谷胱甘肽S-转移酶。肾脏转运体和/或代谢酶介导药物相互作用(DDIs)是临床关注的重要问题。肾脏转运体和代谢酶存在密切协作关系,在肾脏也存在多种相互作用现象(包括转运-转运相互作用,代谢-代谢相互作用和转运-代谢相互作用),其显著影响药物肾脏处置、临床疗效和肾毒性。本文系统阐述了这些相互作用对药物及其代谢物的肾脏排泄、药动学、DDIs和肾毒性的影响。今后需要进一步阐明肾脏转运-代谢相互作用机制,将有助于研究体内药物肾脏处置和DDIs,促进临床合理用药。     

常见药物转运体基因多态性对药动学影响及研究进展

药物转运体在体内药物的吸收（absorption）、分布（distribution）、代谢（metabolism）及排泄（excretion）的过程（ADME）中发挥着关键的作用。转运体在各组织器官的不同分布以及其基因多态性,导致某些药物的吸收、分布、代谢和排泄过程产生明显的个体差异。随着药物基因组学的快速发展,关于转运体基因多态性的研究报道越来越多。本文对近年来人体主要药物转运体基因多态性在药动学和药效学中的影响研究进行综述。     

溶质载体转运体在肿瘤中的表达及其在抗肿瘤药物研究中的现状

溶质载体(SLC)转运体负责各种内源性和外源性化合物的细胞运输，由于其生物学功能和组织特异性表达，SLC转运体不仅在药物处置扮演重要角色，而且在药物-药物相互作用中发挥着重要作用，并具有作为药物递送靶标的巨大潜力。因此，研发SLC转运体的抑制药或促进药、针对SLC转运底物的靶向前药或制剂也成为研究热点。本综述归纳了SLC转运体在肿瘤中的表达现象，首次总结了基于SLC转运体为靶点的靶向抗肿瘤药物(SLC抑制药、SLC前药和靶向SLC纳米制剂)的最新研究进展，为SLC转运体在肿瘤中的研究和应用提供参考。     

转运体介导的食物-药物相互作用

食物与药物之间的相互作用普遍存在,且作用机制也多种多样。目前,研究较多的是单个食物或食物中的某些营养成分通过调节药物转运体或代谢酶的功能从而影响药物的体内过程。食物对药物体内过程的影响包括吸收、分布、代谢、排泄四个方面,并且主要是调节其中参与的药物转运体和代谢酶的功能。转运体介导的食物对药物体内吸收的影响主要是通过调节肠上皮摄取型和外排型的转运体,从而影响药物的吸收;对分布的影响主要是通过调节体内一些屏障中的转运体;对代谢的影响主要是同时调节药物代谢酶和转运体;对排泄的影响是通过调节肾脏和肝脏胆汁排泄的药物转运体,从而影响药物的清除率。因此,转运体介导的食物与药物相互作用直接影响药物治疗的效果。     

有机阴离子转运多肽活性及表达调控的影响因素

有机阴离子转运多肽(organic anion transporting polypeptides,OATP)是一类重要的跨膜摄取转运体,属于溶质转运体(solute carrier,SLC)超家族,以Na+和ATP非依赖方式参与内源物(胆汁酸、胆红素、前列腺素、甲状腺激素和甾体激素结合物)、药物及毒物转运。多种因素(如激素、炎症因子和药物等)会影响OATP的分布、表达及活性,引起底物在组织器官内蓄积的改变,导致食物-药物及药物-药物相互作用。癌组织内OATP分布特性及表达变化可能参与肿瘤的病理过程。表观基因组学调节与OATP的特异性分布有关。本文就参与OATP表达及功能调控的因素进行综述,为药物研发及发病机制的阐明提供线索。     

Lanthanides inhibit the human noradrenaline, 5-hydroxytryptamine and dopamine transporters

Transporters for the monoamine neurotransmitters, including noradrenaline, 5-hydroxytryptamine [5-HT] and dopamine, have twelve transmembrane spanning regions and cotransport Na⁺ and Cl^– ions. Another family of Na⁺-dependent transporters is that containing the Na⁺/glucose and Na⁺/proline cotransporters that are found in the epithelial cells of renal and intestinal brush border membranes. It has been shown that various trivalent lanthanides can substitute for Na⁺ for transport of glucose and proline. The aim of this study was to determine the effects of lanthanides on the activities of the human noradrenaline, 5-HT and dopamine transporters. Cultured cells were incubated for 2min with 10nM ³H-noradrenaline (SK-N-SH-SY5Y human neuroblastoma cells), ³H-5-HT (JAR human placental choriocarcinoma cells) or ³H-dopamine (COS-7 cells transfected with the cDNA of the human dopamine transporter). Specific amine uptake was determined as the difference between accumulation of the amine in the cells in the absence and presence of a corresponding uptake inhibitor. Under both isotonic (150mM NaCl or LiCl or 90mM lanthanide salt) and hypertonic (150mM NaCl + 100mM LiCl, 250mM LiCl or 150mM lanthanide salt) conditions, replacement of Na⁺ by Li⁺, La³⁺, Eu³⁺ or Sm³⁺ abolished the specific uptake of noradrenaline in SK-N-SH-SY5Y cells and replacement of Na⁺ by Li⁺ or Eu³⁺ decreased the specific uptake of 5-HT in JAR cells by 94–100% and that of dopamine in transfected COS-7 cells by 95–99%. The direct effects of Eu³⁺ (with Na⁺ present) on the human noradrenaline transporter in SK-N-SH-SY5Y cells were also examined. Eu³⁺ inhibited noradrenaline uptake into the cells (IC₅₀ 2.6mM) and nisoxetine binding to crude membranes of SK-N-SH-SY5Y cells (IC₅₀ 4.7mM) with similar potencies. Further experiments showed that 4.5mM EuCl₃ in the presence of 150mM Na⁺ caused a 3.5-fold increase in the K_m of noradrenaline and no change in the maximal rate of noradrenaline uptake. EuCl₃ (4.5mM) also caused a pronounced inhibition of the Na⁺-dependent stimulation of noradrenaline uptake by SK-N-SH-SY5Y cells. It can be concluded from these data that, in contrast with the Na⁺/glucose and Na⁺/proline cotransporters, the lanthanides cannot substitute for Na⁺ in the transport of substrates by the monoamine neurotransmitter transporters and that the lanthanides inhibit the latter transporters by interacting with sites of the transporters involved in amine and Na⁺ binding. Received: 15 July 1996 / Accepted: 28 January 1997     

谷氨酸转运体、谷氨酸/胱氨酸转运体与谷氨酸神经细胞毒作用

谷氨酸转运体与谷氨酸／胱氨酸转运体在脑缺血疾病中起重要作用，谷氨酸转运体的结构或功能改变可使细胞间隙的谷氨酸浓度急剧升高，激活NMDA受体产生一系列的表现，同时抑制谷氨酸／胱氨酸转运体对胱氨酸的摄取，介导谷胱苷肽耗竭、氧自由基升高、胞内钙升高、线粒体损伤、细胞色素c释放等神经细胞毒环节，激活半胱天冬酶诱导凋亡。可进一步加重谷氨酸的神经细胞毒作用。     

Clobenpropit,a histamine H3 receptor antagonist/inverse agonist,inhibits [3H]-dopamine uptake by human neuroblastoma SH-SY5Y cells and rat brain synaptosomes

Background

Clobenpropit, a potent antagonist/inverse agonist at the histamine H₃ receptor (H₃R), reduced the cytotoxic action of 6-hydroxydopamine (6-OHDA) in neuroblastoma SH-SY5Y cells transfected with the human H₃R. We therefore set out to study whether this effect involved a receptor-independent action on dopamine transport.

Human organic anion transporter hOAT3 is a potent transporter of cephalosporin antibiotics, in comparison with hOAT1

We examined the substrate specificity of human organic anion transporter (hOAT) 1 and hOAT3 for various cephalosporin antibiotics, cephaloridine, cefdinir, cefotiam, ceftibuten, cefaclor, ceftizoxime, cefoselis and cefazolin by using HEK293 cells stably transfected with hOAT1 or hOAT3 cDNA (HEK-hOAT1, HEK-hOAT3). Additionally, we examined the uptake of various compounds by these transfectants. The mRNA level of hOAT3 in HEK-hOAT3 was about three-fold that of hOAT1 in HEK-hOAT1. Functional expression of hOAT1 and hOAT3 was confirmed by the uptake of p-[14C]aminohippurate and [3H]estrone sulfate, respectively. p-[14C]Aminohippurate, [3H]estrone sulfate, [14C]captopril, [3H]methotrexate, [3H]ochratoxin A, [3H]leucovorin and [3H]cimetidine were shown to be substrates for hOAT1 and hOAT3, and [3H]dehydroepiandrosterone sulfate was shown to be a substrate for hOAT3. All cephalosporin anitibiotics tested were shown to inhibit the uptake of p-[14C]aminohippurate and [3H]estrone sulfate via hOAT1 and hOAT3, respectively, in a dose-dependent manner, and the IC50 values of these antibiotics, except for cefaclor, for the hOAT1-mediated uptake of p-[14C]aminohippurate were within four-fold of those for the hOAT3-mediated uptake of [3H]estrone sulfate. The uptake of cephaloridine, cefdinir and cefotiam by HEK-hOAT3 was 35-50-fold greater than that by control cells. Moreover, the accumulation of the other cephalolsporin antibiotics was significantly greater in HEK-hOAT3 than in control cells. In contrast, the uptake of these antibiotics by HEK-hOAT1 was within two-fold of that by control cells. In conclusion, hOAT3 plays a more important role than hOAT1 in the renal secretion of cephalosporin antibiotics.     

Illuminating the monoamine transporters: Fluorescently labelled ligands to study dopamine,serotonin and norepinephrine transporters

Fluorescence microscopy has revolutionized the visualization of physiological processes in live-cell systems. With the recent innovations in super resolution microscopy, these events can be examined with high precision and accuracy. The development of fluorescently labelled small molecules has provided a significant advance in understanding the physiological relevance of targeted proteins that can now be visualized at the cellular level. One set of physiologically important target proteins are the monoamine transporters (MATs) that play an instrumental role in maintaining monoamine signalling homeostasis. Understanding the mechanisms underlying their regulation and dysregulation is fundamental to treating several neuropsychiatric conditions such as attention deficit hyperactivity disorder (ADHD), anxiety, depression and substance use disorders. Herein, we describe the rationale behind the small molecule design of fluorescently labelled ligands (FLL) either as MAT substrates or inhibitors as well as their applications to advance our understanding of this class of transporters in health and disease.     

Dynamic pattern of gene expression of ZnT-1, ZnT-3 and PRG-1 in rat brain following flurothyl-induced recurrent neonatal seizures

Zinc transporters (ZnTs) and plasticity-related genes (PRGs) both play the key roles in the formation of hippocampal mossy fiber sprouting, which is associated with cognitive deficits following developmental seizures. Here, for the first time, we report the timing of expression pattern of ZnT-1, ZnT-3 and PRG-1 in hippocampus and cerebral cortex following developmental seizures. A seizure was induced by inhalant flurothyl daily in neonatal Sprague–Dawley rats from postnatal day 6 (P6). Rats were assigned into the recurrent-seizure group (RS, seizures induced in 6 consecutive days) and the control group. At 1.5 h, 3 h, 6 h, 12 h, 24 h, 48 h, 7 d and 14 d after the last seizures, the mRNA level was detected using RT-PCR method; PRG-1 protein level was examined by Western blotting analysis. At an early period of 12 h and 48 h after the last seizures, both ZnT-1 and ZnT-3 showed significantly down-regulated mRNA level in the cerebral cortex of RS group than those at the corresponding time point in control group. In the long-term time point of 14 d after the last seizure, ZnT-3 mRNA and PRG-1 protein level in hippocampus were up-regulated while the mRNA level of ZnT-1 down-regulated; in addition, there were up-regulated level of both the mRNA and protein level of PRG-1 and down-regulated mRNA level of ZnT-3 in the cerebral cortex of RS group when compared to the control. Taken together, these dates are consistent with an important role for ZnT-1, ZnT-3 and PRG-1 in the pathophysiology of the long-term adverse effects of recurrent neonatal seizure-induced hippocampal mossy fiber sprouting and cognitive deficit.     

药物转运蛋白功能及应用

细胞膜转运蛋白是一些药物的吸收、分布和消除的决定因素，具有重要的药剂学意义。作为异生物质排出细胞的通道，ABC转运蛋白对大多数现在使用的药物的体内行为产生重要影响，包括治疗肿瘤、艾滋病和微生物感染用药。小肽转运蛋白具有广谱的底物特异性．能够转运大量的口服的结构类似于小肽的药物。由于新的小肽和多肽模拟物类药物的迅速增加，小肽转运蛋白因可能成为药物转运系统而倍受关注。在分子水平加深对药物转运蛋白的理解势必促进药物设计与生物药剂学的发展。     

Renal Transport of Adefovir,Cidofovir, and Tenofovir by SLC22A Family Members (hOAT1, hOAT3, and hOCT2)

Purpose The nephrotoxicity of the nucleotide antivirals adefovir, cidofovir and tenofovir is considered to depend on the renal tubular transport of them. Although it is known that the antivirals are substrates of the human renal organic anion transporter hOAT1 (SLC22A6), there is no information available on other organic ion transporters. The aim of the present study was to investigate whether the other renal organic anion transporter hOAT3 (SLC22A8) and organic cation transporter hOCT2 (SLC22A2) transport the antivirals. Materials and Methods Uptake experiments were performed using HEK293 cells transfected with cDNA of the organic ion transporters. Results The uptake of adefovir, cidofovir and tenofovir in monolayers stably expressing hOAT3 increased time-dependently, compared with control. Probenecid, a typical inhibitor of organic anion transporters, completely inhibited their transport. The amounts of the antivirals taken up by hOAT3 were much lower than those by hOAT1. The transient expression of hOCT2 did not increase uptake of the antivirals. Conclusion These results indicate that adefovir, cidofovir and tenofovir are substrates of hOAT3 as well as hOAT1, but that quantitatively hOAT1 is the major renal transporter for these drugs.     

肠道药物转运体对药物吸收的研究进展

药物与体内各种转运体的相互作用是药物体内药动学性质的决定性因素之一。本文从肠道转运体出发,介绍了它们在药物吸收过程中的作用,旨在利用肠道转运体的作用增加药物向组织器官的靶向分布;利用转运体的作用改变药物的消除途径,从而减轻其毒副作用;利用转运体的作用进行新药设计从而避免药物间有害相互作用的产生;最后通过构建转运体的高通量筛选系统模型,进行新化合物筛选和候选药物的药动学机制研究,为新药的开发和临床合理化给药提供新的策略和思路。