肠道ABC转运体的结构、功能及其调节的研究进展

肠道转运体由于在控制药物吸收、分布和代谢等药物动力学过程中起重要作用,目前已引起研究者的高度重视。根据底物跨膜转运方向转运体分为内转运体和外转运体两类。其中,内转运体主要介导氨基酸、核酸等营养物质的转运;而外转运体主要介导药物排泌,它们主要表达于肠道上皮细胞的顶膜上,能转运阴离子、氨基酸、多肽、糖类分子、维生     

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.     

Caco-2细胞模型在口服药物吸收研究中的应用

目的对Caco 2细胞模型在口服药物肠吸收研究中的应用作一综述。方法在引用了自1974~2004年的32篇文献的基础上,通过介绍并比较体外Caco 2模型和体内药物吸收转运的不同途径,讨论Caco 2单层细胞模型在预测不同类药物体内吸收中的作用。结果Caco 2细胞模型可以预测不同转运途径的药物体内吸收,尤其适用于被动转运药物,这一细胞模型在药物吸收机制、处方组成透膜性和黏膜毒性、药物吸收过程中的相互作用、药物的化学结构和体内转运关系、药物吸收限速因素、药物代谢稳定性及pH对药物吸收的影响等研究中均有较广泛的应用。结论Caco2细胞模型用于预测各种途径的药物吸收,在细胞水平上提供了大量与吸收相关的信息,是口服药物高通量筛选的良好工具。     

基于膜转运体在药物吸收、分布、代谢和排泄过程中功能的药物设计(英文)

膜转运体介导了多种药物的摄取和外排过程, 在药物吸收、分布、代谢和排泄 (ADME) 过程中起了重要作用。膜转运体的独特性质使其成为药物研发中的潜在靶标, 合理利用这一靶标可使药物具有理想的药动学特征包括靶向分布,临床疗效改进和不良反应的降低。本文综述了目前主要的摄取和外排转运体包括溶质转运蛋白 (SLC) 超家族和三磷酸腺苷结合盒超家族 (ABC) 的特异性组织分布, 转运功能和底物谱。例举了几个基于转运体的改良药物ADME特性的成功例子。在本文最后探讨了药物设计研发中常用于研究药物和转运体之间相互作用的体内体外的研究方法。     

血管活性肠肽对HT-29细胞水通道蛋白8表达的影响

<正>结肠的主要功能是吸收食物残渣中的水分和盐类,使粪便成形,结肠内水分的吸收属于被动转运,但近年研究发现消化道水通道蛋白(aquaporins,AQPs)大量表达,提示经细胞途径的水分吸收机制除了简单扩散外还存在特殊跨膜转运蛋白的快速水转运机制。研究认为AQPs在肠道的异常表达导致结肠对水分的吸收和分泌紊乱,参与了腹泻和便秘的发生。     

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。     

药物肠道吸收研究方法

药物在肠道内的吸收程度和吸收特征是影响口服药物生物利用度的重要因素。肠道吸收研究可以预测影响药物在肠道吸收的机制与因素,研究方法主要包括体内法（invivo）、在体法（insitu）、体外法（invitro）等。就目前药物小肠吸收的研究方法及其特点进行综述。     

药物外排泵和转运蛋白对口服药物吸收影响的研究进展

人体肠道的药物外排泵和转运蛋白对口服药物的吸收有较大影响,常见的药物外排泵有P-糖蛋白和多药耐药相关蛋白,会降低相关底物吸收;其它的一些转运蛋白如有机离子转运蛋白家族、H+/单羧酸共转运蛋白和肽转运蛋白可促进相关底物的吸收.作者对药物外排泵和转运蛋白近年来的相关研究进行了综述,并指出了药物外排泵和转运蛋白今后可能的研究方向.     

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。     

小肠首过代谢的研究进展

肠道是口服药物的主要吸收器官,肠道上皮细胞中不仅存在大量影响药物吸收的转运体,还含有多种与肝脏中相同的代谢酶。此外,肠腔细菌丛中也含有大量代谢酶。这些因素使小肠成为肝外最重要的代谢器官。肠道对口服药物的首过代谢作用正逐渐被认识,其对口服药物的吸收和生物利用度的影响成为药物代谢性质评价的重要内容。本文概述了小肠上皮细胞中代谢酶的分布特点和含量,肠腔中菌丛的分布特点和所含代谢酶,并对药物肠道首过效应的国内外研究方法和进展进行了综述。     

Intestinal absorption of drugs mediated by drug transporters: mechanisms and regulation

The absorption of drugs from the gastrointestinal tract is one of the important determinants for oral bioavailability. Development of in vitro experimental techniques such as isolated membrane vesicles and cell culture systems has allowed us to elucidate the transport mechanisms of various drugs across the plasma membrane. Recent introduction of molecular biological techniques resulted in the successful identification of drug transporters responsible for the intestinal absorption of a wide variety of drugs. Each transporter exhibits its own substrate specificity, though it usually shows broad substrate specificity. In this review, we first summarize the recent advances in the characterization of drug transporters in the small intestine, classified into peptide transporters, organic cation transporters and organic anion transporters. In particular, peptide transporter (PEPT1) is the best-characterized drug transporter in the small intestine, and therefore its utilization to improve the oral absorption of poorly absorbed drugs is briefly described. In addition, regulation of the activity and expression levels of drug transporters seems to be an important aspect, because alterations in the functional characteristics and/or expression levels of drug transporters in the small intestine could be responsible for the intra- and interindividual variability of oral bioavailability of drugs. As an example, regulation of the activity and expression of PEPT1 is summarized.     

Contribution of multidrug resistance-associated protein 2 to secretory intestinal transport of organic anions

Various mechanisms can influence the intestinal absorption and oral bioavailability of drugs. The barrier effects of efflux transporters may be one of the critical factors limiting the bioavailability of certain drugs. It has been reported that multidrug resistance-associated protein 2 (Mrp2) is expressed in the mucosal membrane of the epithelium of the small intestine and secretes various drugs into the jejunum lumen. However, it is possible that total intestinal secretion of Mrp2 substrates is accounted for the contribution of Mrp2 and other transporter(s) to the intestinal secretion of Mrp2 substrates. In this study, we found that phenolsulfonphthalein and pravastatin, both Mrp2 substrates, are transported by different transport systems in the intestine. These results suggest that contribution of transporters to the drug transport may be a critical factor affecting drug disposition and drug-drug interaction. In addition to evaluating the substrate specificity of a transporter, it is important to be aware of the contribution of a transporter to drug disposition.     

The transport of organic cations in the small intestine: Current knowledge and emerging concepts

A wide variety of drugs and endogenous bioactive amines are organic cations (OCs). Approximately 40% of all conventional drugs on the market are OCs. Thus, the transport of xenobiotics or endogenous OCs in the body has been a subject of considerable interest, since the discovery and cloning of a family of OC transporters, referred to as organic cation transporter (OCTs), and a new subfamily of OCTs, OCTNs, leading to the functional characterization of these transporters in various systems including oocytes and some cell lines. Organic cation transporters are critical in drug absorption, targeting, and disposition of a drug. In this review, the recent advances in the characterization of organic cation transporters and their distribution in the small intestine are discussed. The results of the in vitro transport studies of various OCs in the small intestine using techniques such as isolated brush-border membrane vesicles, Ussing chamber systems and Caco-2 cells are discussed, and in vivo knock-out animal studies are summarized. Such information is essential for predicting pharmacokinetics and pharmacodynamics and in the design and development of new cationic drugs. An understanding of the mechanisms that control the intestinal transport of OCs will clearly aid achieving desirable clinical outcomes.     

Intestinal solute carriers: an overview of trends and strategies for improving oral drug absorption.

A large amount of absorptive intestinal membrane transporters play an important part in absorption and distribution of several nutrients, drugs and prodrugs. The present paper gives a general overview on intestinal solute carriers as well as on trends and strategies for targeting drugs and/or prodrugs to these carriers in order to increasing oral bioavailability and distribution. A number of absorptive intestinal transporters are described in terms of gene and protein classification, driving forces, substrate specificities and cellular localization. When targeting absorptive large capacity membrane transporters in the small intestine in order to increase oral bioavailabilities of drug or prodrug, the major influence on in vivo pharmacokinetics is suggested to be dose-dependent increase in bioavailability as well as prolonged blood circulation due to large capacity facilitated absorption, and renal re-absorption, respectively. In contrast, when targeting low-capacity transporters such as vitamin transporters, dose independent saturable absorption kinetics are suggested. We thus believe that targeting drug substrates for absorptive intestinal membrane transporters could be a feasible strategy for optimizing drug bioavailability and distribution.     

Oral drug delivery utilizing intestinal OATP transporters

Transporters play important roles in tissue distribution and urinary- and biliary-excretion of drugs and transporter molecules involved in those processes have been elucidated well. Furthermore, an involvement of efflux transporters such as P-glycoproteins, multidrug resistance associated protein 2, and breast cancer resistance protein as the intestinal absorption barrier and/or intestinal luminal secretion mechanisms has been demonstrated. However, although there are many suggestions for the contribution of uptake/influx transporters in intestinal absorption of drugs, information on the transporter molecules responsible for the intestinal absorptive process is limited. Among them, most studied absorptive drug transporter is peptide transporter PEPT1. However, utilization of PEPT1 for oral delivery of drugs may not be high due to the chemical structural requirement of PEPT1 limited to peptide-mimetics. Recently, organic anion transporting polypeptide (OATP) family such as OATP1A2 and OATP2B1 has been suggested to mediate intestinal absorption of several drugs. Since OATPs exhibit species difference in expressed tissues and functional properties between human and animals, human studies are essential to clarify the intestinal absorption mechanisms of drugs via OATPs. Recent pharmacogenomic studies demonstrated that OATP2B1 is involved in the drug absorption in human. In addition, information of drug-juice interaction in the intestine also uncovered the contribution of OATP1A2 and OATP2B1 in drug absorption. Since OATP1A2 and OATP2B1 exhibit broader substrate selectivity compared with PEPT1, their potential to be applied for oral delivery should be high. In this review, current understanding of characteristics and contribution as the absorptive transporters of OATPs in small intestine in human is described. Now, it is getting clearer that OATPs have significant roles in intestinal absorption of drugs, therefore, there are higher possibility to utilize OATPs as the tools for oral delivery.     

Intestinal OCTN2- and MCT1-targeted drug delivery to improve oral bioavailability

Various drug transporters are widely expressed throughout the intestine and play important roles in absorbing nutrients and drugs,thus providing high quality targets for the design of prodrugs or nanoparticles to facilitate oral drug delivery.In particular,intestinal carnitine/organic cation transporter 2(OCTN2)and mono-carboxylate transporter protein 1(MCT1)possess high transport capacities and complementary distributions.Therefore,we outline recent developments in transporter-targeted oral drug delivery with regard to the OCTN2 and MCT1 proteins in this review.First,basic information of the two transporters is reviewed,including their topological structures,characteristics and functions,expression and key features of their substrates.Furthermore,progress in transporter-targeting prodrugs and nanoparticles to increase oral drug delivery is discussed,including improvements in the oral absorption of anti-inflammatory drugs,antiepileptic drugs and anticancer drugs.Finally,the potential of a dual transporter-targeting strategy is discussed.     

Expression of clinically relevant drug‐metabolizing enzymes along the human intestine and their correlation to drug transporters and nuclear receptors: An intra‐subject analysis

The oral bioavailability of many drugs is highly influenced not only by hepatic but also by intestinal biotransformation. To estimate the impact of intestinal phase I and II metabolism on oral drug absorption, knowledge on the expression levels of the respective enzymes is an essential prerequisite. In addition, the potential interplay of metabolism and transport contributes to drug disposition. Both mechanisms may be subjected to coordinative regulation by nuclear receptors, leading to unwanted drug‐drug interactions due to induction of intestinal metabolism and transport. Thus, it was the aim of this study to comprehensively analyse the regional expression of clinically relevant phase I and II enzymes along the entire human intestine and to correlate these data to expression data of drug transporters and nuclear receptors of pharmacokinetic relevance. Gene expression of 11 drug‐metabolizing enzymes (CYP2B6, 2C8, 2C9, 2C19, 2D6, 3A4, 3A5, SULT1A, UGT1A, UGT2B7, UGT2B15) was studied in duodenum, jejunum, ileum and colon from six organ donors by real‐time RT‐PCR. Enzyme expression was correlated with expression data of the nuclear receptors PXR, CAR and FXR as well as drug transporters observed in the same cohort. Intestinal expression of all studied metabolizing enzymes was significantly higher in the small intestine compared to colonic tissue. CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4/5, SULT1A, UGT1A and UGT2B7 expression increased from the duodenum to jejunum but was markedly lower in the ileum. In the small intestine, that is, the predominant site of drug absorption, the highest expression has been observed for CYP3A4, CYP2C9, SULT1A and UGT1A. In addition, significant correlations were found between several enzymes and PXR as well as ABC transporters in the small intestine. In conclusion, the observed substantial site‐dependent intestinal expression of several enzymes may explain regional differences in intestinal drug absorption. The detected correlations between intestinal enzymes, transporters and nuclear receptors provide indirect evidence for their coordinative expression, regulation and function in the human small intestine.     

Intestinal permeability and its relevance for absorption and elimination

Human jejunal permeability (P(eff)) is determined in the intestinal region with the highest expression of carrier proteins and largest surface area. Intestinal P(eff) are often based on multiple parallel transport processes. Site-specific jejunal P(eff) cannot reflect the permeability along the intestinal tract, but they are useful for approximating the fraction oral dose absorbed. It seems like drugs with a jejunal P(eff) > 1.5 x 10(-4) cm s(-1) will be completely absorbed no matter which transport mechanism(s) are utilized. Many drugs that are significantly effluxed in vitro have a rapid and complete intestinal absorption (i.e. >85%) mediated by passive transcellular diffusion. The determined jejunal P(eff) for drugs transported mainly by absorptive carriers (such as peptide and amino acid transporters) will accurately predict the fraction of the dose absorbed as a consequence of the regional expression. The data also show that: (1) the human intestinal epithelium has a large resistance towards large and hydrophilic compounds; and (2) the paracellular route has a low contribution for compounds larger than approximately molecular weight 200. There is a need for more exploratory in vivo studies to clarify drug absorption and first-pass extraction along the intestine. One is encouraged to develop in vivo perfusion techniques for more distal parts of the gastrointestinal tract in humans. This would stimulate the development of more relevant and complex in vitro absorption models and form the basis for an accurate physiologically based pharmacokinetic modelling of oral drug absorption.     

Frog intestinal sac as an in vitro method for the assessment of intestinal permeability in humans: Application to carrier transported drugs

The aim of this study was to investigate the presence of pharmaceutically relevant drug transporters in frog intestine which has been proposed as model for intestinal permeability screening assays of passively absorbed drugs in humans [Trapani, G., Franco, M., Trapani, A., Lopedota, A., Latrofa, A., Gallucci, E., Micelli, S., Liso, G., 2004. Frog intestinal sac: a new in vitro method for the assessment of intestinal permeability. J. Pharm. Sci. 93, 2909-2919]. The expression of transporters in frog intestine was supported by the following observations: (i) the involvement of purine nucleobase transport system was deduced by inhibition of acyclovir transport in the presence of adenine; (ii) baclofen or l-dopa transport was inhibited by the digitalis steroid ouabain and it may be related to the Na(+) electrochemical potential difference, presumably involving amino acid transporters; (iii) the presence of proton-dependent peptide transporters was argued evaluating the effect of the pH change (from pH 5.9 to pH 7.4) on the transport of glutathione; (iv) the possible expression in the frog intestine of an efflux system distinct from P-glycoprotein (Pgp) in the benzylpenicillin transport was deduced using a glucose enriched frog Ringer with or without the known Pgp inhibitor verapamil; (v) the contribution of Pgp-mediated efflux system in determining the frog intestinal absorption of drugs was supported by the specific inhibition of cimetidine or nadolol transport in the presence of verapamil. These results indicate that pharmaceutically relevant drug transporters should be also expressed in frog intestine. In this work, an attempt was also made to compare the measured P(app) values in the frog intestinal model for the aforementioned series of actively/effluxed transported drugs in humans to the corresponding literature values for the fraction absorbed. The P(app) values used in these comparisons were obtained at high concentrations of drugs at which probably saturation of the carrier occurs. Interestingly, it was found that drugs that are completely absorbed had P(app) values >3 x 10(-6)cm/s, while drugs absorbed <90% had P(app) values lower than 1 x 10(-6)cm/s. In these cases, indeed, a borderline region characterized by the apparent permeability coefficient P(app) value between 1 x 10(-6) and 3 x 10(-6)cm/s should be considered for which the prediction of the absorbed fraction after oral administration in humans become more uncertain by the frog intestinal sac system.