肠道CYP3A和P-gp:口服药物的吸收屏障

细胞色素P4 5 0 3A (CYP3A)亚族是人类药物代谢最重要的I相酶。由Mdr1基因编码的外向转运载体蛋白P糖蛋白 (P gp)为药物外排泵。这两种蛋白质在口服药物吸收的主要部位胃肠道均有高表达 ,同时二者的底物具有显著的重叠性。近来 ,大量研究表明 ,决定口服药物生物利用度的主要因素是肠道细胞CYP3A对已吸收药物的生物转化作用和肠道细胞中P gp对已吸收药物的主动外排作用。如果药物为CYP3A和 (或 )P gp的底物 ,当其与CYP3A和P gp的抑制剂同时服用后 ,药物的口服生物利用度将可能升高     

肠道CYP3A和P-gp:口服药物的吸收屏障

细胞色素P4 5 0 3A (CYP3A)亚族是人类药物代谢最重要的I相酶。由MDR1基因编码的外向转运载体蛋白P糖蛋白 (P gp)为药物外排泵。这两种蛋白质在口服药物吸收的主要部位胃肠道均有高表达 ,同时二者的底物具有明显的重叠性。近来 ,大量研究表明 ,决定口服药物生物利用度的主要因素是肠道细胞CYP3A对已吸收药物的生物转化作用和肠道细胞中P gp对已吸收药物的主动外排作用。如果药物为CYP3A和 (或 )P gp的底物 ,当其与CYP3A和P gp的抑制剂同时服用后 ,药物的口服生物利用度将可能升高     

细菌多药外排系统及其研究方法的进展

位于细菌细胞膜上的多药外排泵可将多种结构无关药物排出，本文综述了细菌主要外排泵包括初级和次级转运系统的分子生物学特征及外排蛋白结构与药物识别和转运上的关系；同时总结了对外排蛋白进行结构与功能关系研究的主要的方法，包括定点诱变、螺旋空间排列和结晶等。     

细菌RND外排泵的结构与作用机制研究进展

摘要：细菌RND(resistance-nodulation-cell division)外排泵是一类由内膜转运蛋白、周质融合蛋白、外膜外排蛋白组成的蛋 白复合体,能够将抗菌药物和多种小分子化合物如毒素、染料、洗涤剂、脂质、群感信号分子等排出细菌细胞外。通过影响 RND外排泵的组装和功能,可逆转多重耐药性的发生与防止耐药性的发展。细菌具有多种外排泵,本文以RND外排泵为代表, 介绍与其结构以及外排药物的转运和调控机制的最新进展。     

ABC跨膜转运蛋白外排抑制剂促进药物肠吸收的研究进展

药物的肠吸收受肠道内的外排转运蛋白影响,其中ABC跨膜转运蛋白为目前已知的主要外排转运蛋白。近年开发的可直接抑制转运蛋白外排作用的外排抑制剂大多属于非离子表面活性剂和植物天然成分。本文综述这两类外排抑制剂的研究进展。     

铜绿假单胞菌主动外排泵介导的多重抗生素耐药性

铜绿假单胞菌作为一种机会致病菌，对多种临床常用抗生素呈现明显的固有与获得性耐药。这种多重耐药性的形成机制在于该菌具有的多种能量依赖性的药物主动外排泵和低通透性外膜屏障协同作用所致。近10年对铜绿假单胞菌药物外排泵的研究已经颇为深入，本文对有关进展予以讨论。在铜绿假单胞菌已报道了6种属于“耐药-生节-分裂(RND)”类的药物外排泵系统，它们可在天然野生株表达或者由于基因突变而诱导表达，从而介导了对β-内酰胺类(包括β-内酰胺酶抑制剂)、氨基糖苷类、氟喹诺酮类、大环内酯类及四环素类等的耐药性。这些外排泵中尤其以MexAB—OprM系统的作用底物范围最广，在耐药性形成中起主要作用。RND类外排泵系统也普遍存在于其它革兰氏阴性细菌。各外排泵通常由内膜转运体蛋白、内膜融合蛋白及外膜通道蛋白一起形成功能性转运复合体将药物排至胞外。药物外排泵常影响对灭活酶较稳定的抗菌药物。一些新抗菌药物如Linezolid(Oxa—zolidinoes类)、Telithromyein(Ketolides类)及Tigecycline(Glycyclines类)也是MexAB-OprM等RND类外排泵的作用底物，故这些药物抗革兰氏阳性细菌的活性较强。铜绿假单胞菌外排泵表达的调控机制多是在转录水平上受局部阻遏物或激活物的作用。这些局部调节子的基因突变能导致外排泵活性增强。并常见于应用抗生素或其它抗菌消毒制剂后从临床分离的或实验室筛选的多重耐药铜绿假单胞菌。这些耐药菌的形成再次说明合理限制抗菌药物应用的必要性。外排泵系统还与其它耐药机制如细菌的药物作用靶位改变或产生药物灭活酶等一起发挥明显的协同作用，使细菌的耐药程度进一步地增高。现已研制了针对铜绿假单胞菌等细菌的外排泵抑制剂。应用外排泵抑制剂可阻断药物外排泵这一耐药机制，以维护或提高抗菌药物的抗菌活性。如外排泵抑制剂在体外和动物感染模型均被证实明显增强了氟喹诺酮类对铜绿假单胞菌敏感株和耐药株的抗菌活性，并降低了耐药菌的发生率。外排泵抑制剂尚处于临床前的基础实验研制阶段。     

多重耐药外排泵抑制剂作用机制研究

多重耐药外排泵广泛存在于各种病原菌中,对细菌的药物敏感性以及细菌性感染的临床治疗影响很大。对于细菌来说,外排基因占所有转运蛋白基因的6%～18%,所以外排基因编码的外排泵是导致其多重耐药的重要机制。最新研究结果表明[1-2],临床分离的多重耐药的大肠埃希菌,其耐药性往往与某些基因的超表达相关,     

抗生素耐药性的主动外排机制

细菌对抗生素产生耐药性的机制多种多样，常见的有：细菌产生酶对抗生素的修饰与灭活；药物作用靶点发生改变；膜通透性下降；膜产生主动外排作用；生物被膜的形成。膜的主动外排机制是由各种外排蛋白系统介导的把抗生素等药物从细菌细胞内泵出的主动排出过程，外排系统具有能量依赖性、底物广泛性、系统多样性及功能复杂性的特点；与常用抗生素、合成抗菌药、染料、去污剂及金属离子的多重耐药性密切相关，尤其对四环素、氯霉素及氟喹诺酮类药物等广谱抗菌药的作用更为明显；其生理功能与正常物质转运和代谢有关。以利血平为代表的外排泵抑制剂能有效地对抗主动外排作用的产生，此类抑制剂将是防制细菌多重耐药性的有效措施之一。     

大肠埃希菌多重药物外排泵AcrAB-TolC研究进展

在目前广泛应用抗生素的背景下,细菌耐药已经成了一个世界性的课题。细菌可通过多种途径削弱抗生素的作用,如产生使药物失活的酶,改变代谢途径,产生能隔离药物使其不能结合到作用位点的分子,减少药物摄入以及改变药物作用靶位等[1] 。因此,细菌对目前应用的几乎所有抗生素都能产生不同程度的耐受。必须引起注意的是,近年发现的能引起多重药物耐受(multi drugresistance ,MDR)的外排泵系统在临床耐药中扮演越来越重要的角色。1　细菌药物外排泵及其与耐药性的关系细菌药物外排泵是能将有害底物排除菌体外的一组转运蛋白,是细菌适应环境的表…     

抗生素药性的主动外排机制

细菌对抗生素产生耐药性的机制多种多样，常见的有；细菌产生酶对抗生素的修饰与灭活；药物作用靶点发生改变；膜通透性下降；膜产生主动外排作用；生物被膜的形成，膜的主动外排机制是由各种外排蛋白系统介导的把抗生素等药物从细菌细胞内泵出的主动排出过程，外排系统具有能量依赖性，底物广泛性，系统多样性及功能复杂性的特点；与常用抗生素，合成抗菌药，染料，去污剂及金属离子的多重耐药性密切相关，尤其对四环素，氯霉素及氟喹诺酮类药等广谱抗菌药的作用更为明显；其生理功能与正常物质转运和代谢有关，以利血平为代表的外排泵抑制剂能有效地对抗主动外排作用的产生，此类抑制剂将是防制细菌多重耐药性的有效措施之一。     

Segmental intestinal transporters and metabolic enzymes on intestinal drug absorption.

Recently, a physiologically-based, segregated flow model that incorporates separate intestinal tissue and flow to both a nonabsorptive and an absorptive outermost layer (enterocytes) was shown to better describe the observations on route-dependent morphine glucuronidation in the rat small intestine than a traditional physiologically-based model. These theoretical models were expanded, as the segmental segregated flow model and the segmental traditional model, to view the intestine as three segments of equal lengths receiving equal flows to accommodate heterogeneities in segmental transporter and metabolic functions. The influence of heterogeneity in absorptive, exsorptive, and metabolic functions on drug clearance, bioavailability (F), and metabolite formation after intravenous and oral dosing was examined for the intestine when the tissue was the only organ of removal. Simulations were performed for first-order conditions, when drug partitioned readily (flow-limited distribution) or less readily (membrane-limited distribution) into intestinal tissue, and for different gastrointestinal transit times. The intestinal clearance was found to be inversely related to the rate constant for absorption of a drug that was subjected to secretion and was positively correlated with the metabolic and secretory intrinsic clearances. F was positively correlated with the absorption rate constant but was inversely related to the metabolic and secretory intrinsic clearances. The gastrointestinal transit time decreased metabolite formation, increased clearance, and decreased F. The simulations further showed that a descending metabolic intrinsic clearance yielded a lower F and an ascending segmental distribution of metabolic intrinsic clearance yielded a higher F.     

药物肠吸收的研究方法进展

药物在肠内的吸收过程,是决定口服药物生物利用度的重要因素。科学的肠吸收研究方法可以让我们了解肠上皮细胞和肠内酶对药物吸收的影响,并获得药物在肠道的吸收动力学参数、有效吸收部位、吸收机制、影响吸收的因素等信息。本文对外翻肠囊法、Caco-2细胞模型法、MDCK细胞模型法、平行人造膜通透性测定法、肠灌流法、血管插管法等几种方法,就模型自身及应用作一综述。     

肠道菌群对药物代谢影响的研究进展

肠道菌群是寄居在肠道的种类繁多、数量庞大的微生物群落,对药物等外来化合物的代谢至关重要,近年来肠道菌群作为机体"隐形器官"被广泛关注。通过查阅国内外相关文献,该文对机体中肠道菌群的分类、功能及其对中药化学成分和化学药物代谢的影响进行了分析、归纳和总结。了解肠道菌群对药物代谢的影响,明确药物转化过程,对于指导临床合理用药、个体化用药、毒理学评估及推动药物发现和研发具有重要意义,为后期研究高原环境下肠道菌群对药物代谢的影响提供理论指导。     

Gender-related differences on P-glycoprotein-mediated drug intestinal transport in rats

Objectives Evidence of sex‐related differences on drug pharmacokinetics and pharmacodynamics are markedly increasing. The aim of this study was to characterize the influence of gender on P‐glycoprotein (P‐gp)‐mediated drug intestinal transport using two ex‐vivo methodological approaches. Methods To study the comparative tissue uptake of ivermectin, intestinal sacs (distal jejunum/ileum) of male and female Wistar rats were incubated with ivermectin (0.5 µm ) (a P‐gp substrate) in the presence or absence of PSC833 (10 µm ) (a P‐gp inhibitor). Additionally, sex‐based differences in the bidirectional transport of Rhodamine 123 (Rho 123; 5 µm ) incubated either alone or with PSC833 (10 µm ) were examined in diffusion chambers. Key findings The ivermectin accumulation in the everted gut sacs was higher in female compared with male intestine. The presence of PSC833 increased ivermectin accumulation profiles both in male and female rats. However, a greater response to transport modulation was observed in male compared with female animals. Similar results were obtained for Rho 123, where a higher absorption was measured in the intestine of females. PSC833 decreased Rho 123 intestinal secretion in animals of both sexes with a greater inhibition in male. Conclusions Substantial sex‐related differences were observed on the ivermectin and Rho 123 active intestinal transport. Likewise, the PSC833‐mediated modulation had a differential impact between male and female animals. Further work is needed to clarify the mechanisms underlying this phenomenon, which may have considerable pharmacological and clinical relevance.     

Effects of Chinese herbal medicines on intestinal drug absorption

Sho-saiko-to (Xiao-Chai-Hu-Tang), one of the major traditional Chinese medicines, has been frequently prescribed with other synthetic or biotechnological drugs for the treatment of various acute or chronic diseases in Japan, and thus it is important to understand the interactions between Sho-saiko-to and coadministered drugs. This paper reviews the effects of Sho-saiko-to on the pharmacokinetics and pharmacodynamics of concomitant drugs in the gastrointestinal tract. Sho-saiko-to slightly hastens the gastrointestinal absorption of the sulfonylurea compound tolbutamide. Furthermore, it is considered that the increase in the gastrointestinal absorption rate by Sho-saiko-to may potentiate the hypoglycemic effects of tolbutamide in the early period after oral administration. Sho-saiko-to can facilitate the epithelial membrane permeability of tolbutamide at an early phase across the rat jejunum in situ and Caco-2 cell monolayers. It is also suggested that Sho-saiko-to enhances the energy-dependent transport of tolbutamide and has an inhibitory effect on the passive paracellular transport of tolbutamide in Caco-2 cells. This result might be related to the accelerated in vivo absorption rate of tolbutamide by concomitant dosing with Sho-saiko-to in rats. In addition, Sho-saiko-to has inhibitory effects on the efflux pump mediated by MDR1, and it appears that the crude constituents in Glycyrrhizae radix, glycyrrhizic acid and liquiritin, contribute to MDR1 suppression.     

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。     

Animal models and intestinal drug transport

BACKGROUND: Intestinal drug metabolism and transport are now well recognized determinants of drug disposition in humans. During the last decade, various animal models lacking drug transporters have been generated in order to investigate the role of transporters for drug absorption, distribution and elimination. OBJECTIVE: In this review the use of the animal models for the investigation of intestinal drug transport will be discussed. METHODS: Publications describing the use of knockout animals (e.g., P-glycoprotein, Bcrp, and Oct1) regarding intestinal drug transport and animals characterized by mutations in transporters genes (e.g., Mrp2) were mainly considered for this review. RESULTS/CONCLUSION: Knockout mouse models for ABC transporters are highly valuable tools to investigate the role of intestinal efflux transporters for the bioavailability of various compounds.