有机阴离子转运肽在药物转运中的作用

溶质运载蛋白家族(solute carrier family,SLC)和ATP结合盒转运蛋白家族(ATP binding cas-sette family,ABC)在药物吸收、消除和组织分布中起重要作用。本综述将对有机阴离子转运肽(or-ganic anion transporting polypeptide,OATP)的最新命名、分类、组织分布、功能及在药物转运中的作用加以介绍。     

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.     

药物肝胆转运实验方法的研究进展

［摘要］依据近年来国内外的相关文献，对细胞水平上研究药物肝胆转运的实验方法进行了综述。肝胆中转运蛋白对药物肝胆转运起着重要作用，影响着临床联合用药的疗效，对药物新剂型的设计也起着指导作用。     

药物与肠道肽转运蛋白PEPT1的相互作用及影响因素

H^＋协同转运载体PEPT1主要存在于小肠上皮细胞的刷状缘膜上，肠道PEPT1对于消化道中蛋白质的降解产物二肽、三肽具有转运吸收的功能，另外肽类似药物如β-内酰胺类抗生素、血管紧张素转化酶抑制剂、非肽药物伐昔洛韦等也经此载体转运吸收。肠道PEPT1对于维持机体的内环境稳定以及药物的胃肠道吸收发挥重要作用。随着对PEPT1基因序列、蛋白结构、功能活性等方面研究的逐渐深入，对于调控PEPT1在膜上表达、影响其功能活性以及与底物亲和力的因素及相关的作用机制有了一定的了解，加之PEPT1广泛的底物专属性，使其成为新药开发中重要的药物传递的靶蛋白。了解药物与肠道肽转运蛋白PEPT1的相互作用及其影响因素，对于了解药物一药物相互作用，提高药物口服吸收的生物利用度，研究抗肿瘤药物的靶向治疗以及个体化给药等方面具有十分重要的意义。     

药物传递靶蛋白寡肽转运蛋白1的研究进展

目的:为相关临床安全用药和新药研发提供依据。方法:根据文献,综述了寡肽转运蛋白1(PEPT1)的组织分布、分子结构与功能、转运机制、底物、与药物相互作用等方面的内容。结果:PEPT1主要在小肠表达,肝和肾中表达较少;其基因编码的蛋白上有多个N-糖基化和蛋白激酶的识别位点,它们可能参与肽转运的调控,且其上的His-57是最关键的组氨酸残基,可能是转运蛋白发挥吸收功能时最关键的结合位点;其对大多数的二肽和三肽有高亲和性,能转运某些特定四肽,但不能转运更长的肽段;其转运机制为主动转运;其底物为二肽、三肽化合物等,但不包括氨基酸和四肽以上的大分子;其主要介导口服给药的肽类及肽类似物相关药物的相互作用。结论:虽然现国内有关PEPT1的研究才刚起步,但由于PEPT1具有底物丰富,能够转运亲脂性的、带电荷的以及不同大小的药物分子的特点,使其将会成为设计前药很好的靶蛋白。     

肝脏转运蛋白在药物肝胆转运中的作用

目的对肝脏转运蛋白在药物肝胆转运中的作用作一综述,为药物肝靶向提供依据。方法根据文献,从药物不良反应、药物的矢量转运、药物肝靶向性、药物之间相互作用4个方面阐述肝脏转运蛋白对药物肝胆排泄产生的影响。结果肝脏转运蛋白引起的药物矢量转运影响药物的肝脏摄取,药物肝靶向性影响药物的疗效,药物之间相互作用影响临床用药安全和不良反应。结论肝脏转运蛋白在药物肝胆转运中起到了重要的作用,它与药物在体内各组织分布、临床疗效均有密切的联系。     

小肠寡肽转运蛋白及其在提高药物口服吸收中的应用

小肠上皮细胞刷状缘侧的寡肽转运蛋白(PEPT1)以及侧底膜的寡肽转运蛋白是寡肽转运蛋白(PEPT)的2种亚型,它们在寡肽及拟肽类药物(peptidomimetic drug)肠转运中发挥重要作用。通过前体药物(prodrug)设计将一些吸收差的药物修饰成类似二肽或三肽的结构,在PEPT1的介导下吸收,能够提高这些药物的口服生物利用度,这是非常有意义的。     

肝脏、小肠、脑和肾脏中的转运子在药物消除和组织选择性分布中的作用

转运子在药物的体内处置过程中发挥着重要作用。多种转运子，如有机阴离子转运多聚肽、有机阴离子转运子及多药耐药相关蛋白以其广泛的底物特弄性和转运子基因产物的多样性参与到机体的解毒系统中。由于转运子的组织选择性表达和底物特异性，转运子将在小分子药物向靶组织的传输中发挥重要作用。此外，多药耐药相关蛋白通过把它们的底物转运到组织外，从而在小肠、血脑屏障和血脑脊液屏障中发挥屏障作用。本文叙述了转运子的组织选择性分布及其在药物消除过程中的作用研究进展。     

有机阴离子转运多肽及其对药物吸收、分布和排出的影响

药物在体内的转运正日益被认为是影响药效和药物残留的关键因素.近年来研究表明位于细胞膜上的转运蛋白在药物的吸收、分布和排出中发挥重要作用,药物在组织间的定向运动依赖于药物吸收和排出转运蛋白的协同作用.有机阴离子转运多肽(OATP)是一类药物吸收转运蛋白,在药物吸收、组织分布及其在肝、肾的清除中起重要作用.本文就近年来对OATP结构特点、生物学功能的研究进行综述.     

喹诺酮类抗菌药转运机制研究

抗菌药物的疗效受病原体耐药、体内药物浓度及药物－药物相互作用等多种因素影响，而药物的转运方式及相应的载体蛋白对药物的疗效具有重要的作用。因此，本文对喹诺酮类抗菌药的转运机制及可能参与的载体蛋白进行收集与探讨。     

Transport of peptidomimetic drugs by the intestinal Di/tri-peptide transporter,PepT1

The apical membrane of small intestinal enterocytes possess an uptake system for di- and tripeptides. The physiological function of the system is to transport small peptides resulting from digestion of dietary protein. Moreover, due to the broad substrate specificity of the system, it is also capable of transporting a number of orally administered peptidomimetic drugs. Absorbed peptides may be hydrolysed in the cells due to the high peptidase activity present in the cytosol. Peptidomimetic drugs may, if resistant to the cellular enzyme activity, pass the basolateral membrane via a basolateral peptide transport mechanism and enter the systemic circulation. As the number of new peptide and peptidomimetic drugs are rapidly increasing, the peptide transport system has gained increasing attention as a possible drug delivery system for small peptides and peptide-like compounds. In this paper we give an updated introduction to the transport system and discuss the substrate characteristics of the di/tri-peptide transporter system with special emphasis on chemically modified substrates and prodrugs.     

Transport of Peptidomimetic Drugs by the Intestinal Di/tri‐peptide Transporter,PepT1

Abstract: The apical membrane of small intestinal enterocytes possess an uptake system for di‐ and tripeptides. The physiological function of the system is to transport small peptides resulting from digestion of dietary protein. Moreover, due to the broad substrate specificity of the system, it is also capable of transporting a number of orally administered peptidomimetic drugs. Absorbed peptides may be hydrolysed in the cells due to the high peptidase activity present in the cytosol. Peptidomimetic drugs may, if resistant to the cellular enzyme activity, pass the basolateral membrane via a basolateral peptide transport mechanism and enter the systemic circulation. As the number of new peptide and peptidomimetic drugs are rapidly increasing, the peptide transport system has gained increasing attention as a possible drug delivery system for small peptides and peptide‐like compounds. In this paper we give an updated introduction to the transport system and discuss the substrate characteristics of the di/tri‐peptide transporter system with special emphasis on chemically modified substrates and prodrugs.     

Current perspectives on established and putative mammalian oligopeptide transporters

Peptides and peptide-based drugs are increasingly being utilized as therapeutic agents for the treatment of numerous disorders. The increasing development of peptide-based therapeutic agents is largely due to technological advances including the advent of combinatorial peptide libraries, peptide synthesis strategies, and peptidomimetic design. Peptides and peptide-based agents have a broad range of potential clinical applications in the treatment of many disorders including AIDS, hypertension, and cancer. Peptides are generally hydrophilic and often exhibit poor passive transcellular diffusion across biological barriers. Insights into strategies for increasing their intestinal absorption have been derived from the numerous studies demonstrating that the absorption of protein digestion products occurs primarily in the form of small di- and tripeptides. The characterization of the pathways of intestinal, transepithelial transport of peptides and peptide-based drugs have demonstrated that a significant degree of absorption occurs through the role of proteins within the proton-coupled, oligopeptide transporter (POT) family. Considerable focus has been traditionally placed on Peptide Transporter 1 (PepT1) as the main mammalian POT member regulating intestinal peptide absorption. Recently, several new POT members, including Peptide/Histidine Transporter 1 (PHT1) and Peptide/Histidine Transporter 2 (PHT2) and their splice variants have been identified. This has led to an increased need for new experimental methods enabling better characterization of the biophysical and biochemical barriers and the role of these POT isoforms in mediating peptide-based drug transport.     

Molecular Trojan horses for blood-brain barrier drug delivery

Peptides and recombinant proteins such as neurotrophins, enzymes and monoclonal antibodies, have not been developed as new drugs for the brain because these large molecule drugs do not cross the brain capillary wall, which forms the blood-brain barrier (BBB) in vivo. A new solution to the brain drug delivery problem is the genetic engineering of recombinant fusion proteins. The therapeutic peptide or protein drug is fused to a molecular Trojan horse, which is a second peptide or peptidomimetic monoclonal antibody that binds a specific receptor on the BBB. The Trojan horse enables receptor-mediated delivery of the fusion protein across the BBB so that the protein drug can enter the brain and exert the desired pharmacological effect.     

CHO/hPEPT1 cells overexpressing the human peptide transporter (hPEPT1) as an alternative in vitro model for peptidomimetic drugs

The present study characterized Chinese hamster ovary cells overexpressing a human intestinal peptide transporter, CHO/hPEPT1 cells, as an in vitro model for peptidomimetic drugs. The kinetic parameters of Gly-Sar uptake were determined in three different cell culture systems such as untransfected CHO cells (CHO-K1), transfected CHO cells (CHO/hPEPT1) and Caco-2 cells. Vmax in CHO/hPEPT1 cells was approximately 3-fold higher than those in Caco-2 cells and CHO-K1 cells, while Km values were similar in all cases. The uptake of beta-lactam antibiotics in CHO/hPEPT1 cells was three to twelve fold higher than that in CHO-K1 cells, indicating that CHO/hPEPT1 cells significantly enhanced the peptide transport activity. However, amino acid drugs also exhibited high cellular uptake in both CHO-K1 and CHO/hPEPT1 cells due to the high background level of amino acid transporters. Thus, cellular uptake study in CHO/hPEPT1 cells is not sensitive enough to distinguish the peptidyl drugs from amino acid drugs. The potential of CHO/hPEPT1 cells as an in vitro model for peptidomimetic drugs was also examined through the inhibition study on Gly-Sar uptake. Peptidomimetic drugs such as beta-lactam antibiotics and enalapril significantly inhibited Gly-Sar uptake whereas the nonpeptidyl compounds, L-dopa and alpha-methyldopa, did not compete with Gly-Sar for cellular uptake within the therapeutic concentrations. In conclusion, the present study demonstrates the further characterization of CHO/hPEPT1 cells as an uptake model as well as inhibition study and suggests their utility as an alternative in vitro model for drug candidates targeting the hPEPT1 transporter.     

Proteomic analysis of small intestinal epithelial cells in antibiotic-treated mice: Changes in drug transporters and metabolizing enzymes

Antibiotics act on bacterial flora originally present in the intestine, and changes in the intestinal flora have various effects on the host. This study investigated changes in the protein levels of drug transporters and metabolizing enzymes in the small intestines of antibiotic-treated mice by proteomic analysis. After the oral administration of non-absorbable antibiotics (vancomycin and polymyxin B) for 5 days, 15 drug transporter or metabolizing enzyme proteins had significantly changed levels among 1780 proteins identified in small intestinal epithelial cells. Of these, the levels of peptide transporter 1 (Pept1), multidrug resistance protein 1a (Mdr1a), and multidrug resistance-associated protein 2 (Mrp2) were increased approximately 2-fold. In addition, the levels of two Cyp4f proteins were decreased and those of Cyp4b1, Ces1d, and three glutathione S-transferase (Gst) proteins were increased. Our results indicate that the oral administration of antibiotics changes the levels of proteins related to the absorption and metabolism of drugs in the small intestine, and suggest that substrate drugs of these proteins have a risk for indirect drug interactions with antibacterial drugs via the intestinal flora.     

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.     

Genetic polymorphisms of ATP-binding cassette transporters ABCB1 and ABCG2: therapeutic implications

Pharmacogenomics, the study of the influence of genetic factors on drug action, is increasingly important for predicting pharmacokinetics profiles and/or adverse reactions to drugs. Drug transporters, as well as drug metabolism play pivotal roles in determining the pharmacokinetic profiles of drugs and their overall pharmacological effects. There is an increasing number of reports addressing genetic polymorphisms of drug transporters. However, information regarding the functional impact of genetic polymorphisms in drug transporter genes is still limited. Detailed functional analysis in vitro may provide clear insight into the biochemical and therapeutic significance of genetic polymorphisms. This review addresses functional aspects of the genetic polymorphisms of human ATP-binding cassette transporters, ABCB1 and ABCG2, which are critically involved in the pharmacokinetics of drugs.