肾脏转运体介导抗病毒药物肾排泄的研究进展

目的:了解肾脏转运体介导抗病毒药物肾排泄的研究现状,为临床合理用药提供参考.方法:对近年抗病毒药物与肾脏转运体相关的文献进行综述.结果:有机阴离子转运体(Organic Anion Transporters,OAT1～3)和有机阳离子转运体(Organic Cation Transporters,OCT1～3)介导药物流入细胞内,而ATP结合转运体(ATP Binding Cassette,P-gp,MRP2～5)介导药物从细胞排出.寡肽转运体(Peptide Transporters,PEPT1～2)介导伐昔洛韦双向扩散.结论:通过介导药物的摄取和排出,肾脏转运体在调节体内常用抗病毒药物浓度时发挥重要的作用.     

HMG—CoA还原酶抑制药与转运体OATP1B1

长期以来药物代谢一直被认为是药物分布过程中的主要决定因素。然而，近年来的研究不断证实膜转运体也具有同样重要的作用。事实上，许多外向转运体如MDR1基因编码的P糖蛋白在药物体内分布和药物效应方面的作用已被广泛而深入的加以研究。一些药物在胃肠道、肝和肾脏等许多器官的定向运动中需要内向和外向转运体来协调转运。例如，在外向转运体介导的药物代谢和经胆道排泄之前，分布在肝细胞基底膜上的内向转运体一一有机阴离子转运体超家族（organic anio-transporting polypeptides，OATPs），可促进药物在细胞内集聚。     

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。     

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。     

转运体在药物胆汁排泄中的作用

目的:综述转运体在药物胆汁排泄中的作用。方法:以近几年国内外研究文献为基础,从转运体介导药物的胆汁排泄过程、介导药物胆汁排泄的转运体、药物相互作用、转运体的基因多态性等方面进行综述。结果:转运体对药物体内经胆汁排泄过程、临床用药安全性、用药后的个体差异等方面均存在影响。结论:随着对转运体认识的不断深入,其将在药物设计、临床合理用药、个体化治疗等方面发挥重要作用。     

肾脏有机阳离子转运体家族研究进展

肾脏转运体在肾脏处置药物过程中发挥重要作用.临床所用药物与肾脏有机阳离子转运体家族密切相关.本文对肾脏有机阳离子转运体家族的主要成员及其特征、影响因素以及实验方法等研究进展进行综述.     

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。     

与肝肠循环相关的转运体及其基因多态性

药物穿过磷脂双分子层是其发挥作用和消除的重要步骤.转运体是一种穿过细胞膜磷脂双分子层的特殊蛋白,它通过主动和/或被动过程介导药物的跨膜转运.转运体在诸多参与体内药物、营养物质代谢及消除过程的组织和器官中都有表达.例如表达于小肠的转运体对于药物的吸收起重要作用;表达于肝细胞表面的不同类型转运体,可以介导药物进入肝细胞或排入胆汁;而表达于肾脏的转运体则可以参与药物的排泄.肝肠循环(enterohepatic circulation,EHC)是药物经胆汁排泄和小肠重吸收的过程,也有一些药物如霉酚酸以结合型代谢物排入肠道后再水解为原形药物重新吸收.EHC可能导致血药浓度的多重峰或半衰期的延长,进而影响药效.小肠和肝脏是药物EHC的重要器官,其中转运体对药物的EHC发挥着重要作用,转运体的表达和功能存在显著个体差异,本文将讨论肝脏和小肠中与EHC过程相关的主要转运体及基因多态性对其表达及功能的影响.     

肾脏转运体及其研究方法

肾脏是机体重要器官之一,主要承担着体内代谢产物、药物以及毒物等物质的排泄。因此明确各物质在肾脏排泄机制有利于提高药物的安全性,避免不良反应,可为指导临床合理用药提供理论依据。本文介绍了肾脏中介导药物分泌与重吸收的转运体,阐述了通过体内、体外方法预测药物经肾脏转运体在肾脏的转运以及排泄机制。此外,还概括了研究肾脏转运体的主要研究方法,为基础以及临床实验提供参考。     

药物转运体介导的中药及单体药物相互作用的研究进展

药物转运体在中药及单体成分的体内吸收、分布和排泄过程中发挥着重要的作用。中药及单体对药物转运体的功能和表达可产生诱导或抑制作用,从而影响这些转运体底物的体内处置过程。随着中药药动学的发展,基于转运体介导的中药及单体体内处置研究越来越受到重视。该文对药物转运体介导的中药及单体药动学的研究进行综述。     

Organic anion transporter family: current knowledge

Organic anion transporters (OATs) play an essential role in the elimination of numerous endogenous and exogenous organic anions from the body. The renal OATs contribute to the excretion of many drugs and their metabolites that are important in clinical medicine. Several families of multispecific organic anion and cation transporters, including OAT family transporters, have recently been identified by molecular cloning. The OAT family consists of six isoforms (OAT1 - 4, URAT1, and rodent Oat5) and they are all expressed in the kidney, while some are also expressed in the liver, brain, and placenta. The OAT family represents mainly the renal secretory and reabsorptive pathway for organic anions and is also involved in the distribution of organic anions in the body, drug-drug interactions, and toxicity of anionic substances such as nephrotoxic drugs and uremic toxins. In this review, current knowledge of and recent progress in the understanding of several aspects of OAT family members are discussed.     

Activation of ATP-sensitive K+ channels by ADP and K+ channel openers: homology model of sulfonylurea receptor carboxyl-termini

The multispecific organic anion transporters have been indicated to be involved in the transmembrane transport of various anionic substances. The kidney and liver possess the distinct organic anion transport pathways for the elimination of potentially toxic anionic drugs and metabolites. In the kidney, proximal tubular cells actively excrete organic anions of both endogenous and exogenous origin. We have isolated the renal multispecific organic anion transporter, OAT1 (organic anion transporter 1), from the rat kidney. OAT1 is a 551-amino acid residue protein with 12 putative membrane spanning domains. OAT1 mediates sodium-independent, anion exchange for a variety of organic anions including p-aminohippurate, cyclic nucleotides, prostanoides, dicarboxylates, and anionic drugs including beta-lactams, non-steroidal antiinflammatory drugs, diuretics and antiviral drugs. So far, three other isoforms have been identified. OATs comprise a new family of multispecific organic anion transporter, i.e., the OAT family. OATs show weak structural similarity to organic cation transporters (OCTs) and OCTN/carnitine transporters. All of the members of the OAT family are commonly expressed in the kidney, suggesting its significance in the renal organic anion excretion. In addition, OAT members appear to be responsible for the distribution/elimination of water soluble anionic drugs into/from the liver, brain and fetus.     

寡肽转运体PEPT2在药物肾脏转运中的作用和活性调节

目的：研究肽转运体在药物肾脏转运中的作用和活性调节.方法：通过文献检索和分析,对肽转运体PEPT2的转运作用和活性调节进行探讨.结果：肾小管上分布的药物转运体参与了多种药物在肾脏的重吸收和分泌过程,PEPT2的活性在糖尿病或者慢性肾衰等疾病的情况下会上调.结论：随着PEPT2的结构、分布、转运作用和对其作用发挥的影响因素的进一步研究,对于它们在多肽类药物肾脏排泄中的作用有了更为深刻的了解,使其成为新药开发中重要的药物转运体.     

Transporters involved in the elimination of drugs in the kidney: organic anion transporters and organic cation transporters

Transporters in the kidney mediate the secretion or reabsorption of many compounds and thereby influence the plasma levels of their substrates. Organic anion transporters and organic cation transporters are two major classes of secretory transporters in the mammalian kidney. During the past decade, significant progress has been made in the cloning, functional expression, and initial characterization of these transporters. To date, five organic cation transporters and nine organic anion transporters have been cloned. In this review, we summarize the available data on organic anion and organic cation transporters, focusing in particular on their molecular characteristics, tissue distribution, and inhibitor and substrate selectivities. Currently we have a good understanding of the inhibitor selectivities for most of these transporters, and with the development of more robust assays, we will soon have a better understanding of their substrate selectivities. Based on the available data, summarized in this review, it appears that many compounds interact with multiple transporters. Furthermore, there appears to be substantial overlap in the selectivities of organic cation transporters, and the same appears true for organic anion transporters. At the present time, it is unclear what the roles of these multiple transporters are in renal drug elimination. With the development of new assays, reagents, and experimental methods, we will soon have a better understanding of the roles of each transporter isoform in the renal elimination of drugs.     

Renal Organic Anion Transporters (SLC22 Family): Expression, Regulation, Roles in Toxicity, and Impact on Injury and Disease

Organic solute flux across the basolateral and apical membranes of renal proximal tubule cells is a key process for maintaining systemic homeostasis. It represents an important route for the elimination of metabolic waste products and xenobiotics, as well as for the reclamation of essential compounds. Members of the organic anion transporter (OAT, SLC22) family expressed in proximal tubules comprise one pathway mediating the active renal secretion and reabsorption of organic anions. Many drugs, pesticides, hormones, heavy metal conjugates, components of phytomedicines, and toxins are OAT substrates. Thus, through transporter activity, the kidney can be a target organ for their beneficial or detrimental effects. Detailed knowledge of the OATs expressed in the kidney, their membrane targeting, substrate specificity, and mechanisms of action is essential to understanding organ function and dysfunction. The intracellular processes controlling OAT expression and function, and that can thus modulate kidney transport capacity, are also critical to this understanding. Such knowledge is also providing insight to new areas such as renal transplant research. This review will provide an overview of the OATs for which transport activity has been demonstrated and expression/function in the kidney observed. Examples establishing a role for renal OATs in drug clearance, food/drug–drug interactions, and renal injury and pathology are presented. An update of the current information regarding the regulation of OAT expression is also provided.     

Drug-drug interactions involving membrane transporters in the human kidney

The kidneys play a critical role in the elimination of xenobiotics. Factors affecting the ability of the kidney to eliminate drugs may result in marked changes in the pharmacokinetics of a given compound. Drug-drug interactions due to competitive inhibition of renal organic anion or cation secretion systems have been noticed clinically for a long time. However, our understanding of the physical sites of interactions, that is, the specific transport proteins that the interacting drugs act on, has just begun very recently. This review summarises the latest progress in molecular identification and functional characterisation of major drug transporters in the human kidney. In particular, the review focuses on relating cloned renal drug transporters to clinically observed drug-drug interactions. The authors' opinion on the current status and future directions of research in these areas is also offered.     

Mechanisms of renal anionic drug transport

By utilizing filtration, active secretion and reabsorption processes, the kidney can conserve essential nutrients, and eliminate drugs and potentially toxic compounds. Active uptake of organic anions and cations across the basolateral membrane, and their extrusion into the urine across the brush border membrane mainly takes place in the renal proximal tubule cells, and is facilitated via a range of substrate-specific tubular transporters. Many drugs and their phase II conjugates are anionic compounds, and therefore renal organic anion transporters are important determinants of their distribution and elimination. Competition for renal excretory transporters may cause drugs to accumulate in the body leading to toxicity, which is a potential hazard of concomitant drug administration. Here, we present a brief update on the most prominent human proximal tubule organic anion transporters, which either belong to the ATP-binding cassette (ABC) or the solute carrier transporter (SLC) families. We focus on the participation of the individual transporters in renal anionic drug elimination, in an attempt to understand their overall biological and pharmacological significance, hoping to inspire further studies in the renal transporters field.