血脑屏障上的P-糖蛋白与药物转运功能

目的:综述脑毛细血管内皮细胞上的P -糖蛋白药物外排功能。方法:根据对有关的资料的分析、归纳、总结得出P -糖蛋白与脑内药物转运的关系。结果:血脑屏障上的P -糖蛋白具有ATP依赖性的药物外排泵的功能,能降低脑内药物的浓度。结论:利用多药耐药性逆转剂有可能提高脑内的药物转运或者降低药物的通透性减少中枢神经系统的不良反应     

血脑屏障上的P-糖蛋白与药物转运功能

目的：综述脑毛细血管内皮细胞上的Ｐ－糖蛋白药物外排功能。方法：根据对有关的资料的分析,归纳,总结得出Ｐ－糖蛋白与脑内药物转运的关系。结果：血脑屏幕上的Ｐ－糖蛋白具有ＡＴＰ依赖性的药物外排泵的功能,能降低脑内药物的浓度。结论：利用多药耐药性逆转剂有可能提高脑内的药物转运或者降低药物的通透性减少中枢神经系统的不良反应。     

P-糖蛋白药物外排作用的研究进展

P-糖蛋白是一个ATP依赖性外排泵,在多药耐药肿瘤细胞和血脑屏障上均有高度表达。P-糖蛋白的药物外排作用参与了肿瘤多药耐药性,降低了药物在脑内的浓度。P-糖蛋白抑制剂则可以抑制P-糖蛋白的药物外排作用,从而逆转肿瘤多药耐药性,增加药物的脑摄取量。     

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.     

P-糖蛋白及肿瘤多药耐药的逆转

目的:为开发出安全、有效、低毒的P-糖蛋白抑制剂提供参考,以便在临床应用中有效地逆转肿瘤多药耐药,使药物充分发挥其作用以达到治疗疾病的目的。方法:对P-糖蛋白的分布、转运机制、功能、底物及P-糖蛋白在肿瘤多药耐药逆转方面的研究进展作一概述。结果与结论:P-糖蛋白在抑制与诱导P-糖蛋白介导的药物-药物相互作用中具有重要的临床意义,有效的P-糖蛋白抑制剂可抑制P-糖蛋白的药物外排作用,进而逆转肿瘤MDR。     

洛美利嗪对大鼠脑微血管内皮细胞上P-糖蛋白活力的影响与P-gp及mdr1基因mRNA表达无关

目的：研究洛美利嗪对原代培养的大鼠脑微血管内皮细胞（RBMECs）上P-糖蛋白（P-gP）功能和表达的影响。方法：使用流式细胞术分析洛美利嗪对P-gp底物-罗丹明123（rhodaminel23，Rh123）在RBMECs中外排的影响，使用流式细胞术分析了洛美利嗪对RBMECs上P-gp表达的影响，应用RT-PCR技术分析了洛美利嗪对RBMECs mdr1基因mRNA水平表达的影响，还使用Transwell模型研究了洛美利嗪对Rh123通透RBMECs单层细胞转运的影响。结果：洛美利嗪通过抑制了RBMECs胞内Rh123的外排；洛美利嗪对P—gP功能的影响与RBMECs上P-gp及mdr1基因mRNA表达无关；在Transwell模型中，洛美利嗪还能显著增加Rh123跨RBMECs单层细胞膜的、经上室至下室的转运，并抑制相反方向的Rh123的转运。结论：洛美利嗪能显著地抑制RBMECs上P-gp的活性，并对P-gp底物的跨细胞转运产生影响。     

P-糖蛋白抑制剂对蝙蝠葛碱跨膜转运的影响

目的 研究Caco-2细胞模型中P-糖蛋白抑制剂对蝙蝠葛碱跨膜转运的影响.方法 采用HPLC法测定转运液中蝙蝠葛碱的含量;采用Caco-2细胞模型双向转运实验,考察不同浓度维拉帕米、环孢素A和醋酸地塞米松3种p-糖蛋白抑制剂对蝙蝠葛碱跨膜转运的影响.结果 加入3种P-糖蛋白抑制剂后,蝙蝠葛碱的Papp(A-B)均有一定程度增加,而Papp(B-A)均有显著降低(P＜0.05),即均抑制了蝙蝠葛碱的外排转运.结论 外排转运体P-糖蛋白对蝙蝠葛碱有外排作用,蝙蝠葛碱可能为P-糖蛋白底物.     

灵芝多糖肽对Caco-2细胞上P糖蛋白功能、表达的影响

目的 研究灵芝多糖肽(ganoderma lucidum polysaccharides peptide,GLPP)对Caco-2细胞P糖蛋白(P-gp)功能和表达的影响.方法 用流式细胞仪测定Caco-2细胞中P-gp底物罗丹明123和抗体的荧光强度,分析药物对P-gp功能和表达的影响.双向跨膜转运实验考查GLPP对罗丹明123转运的影响.结果 10、20、50、100μg·mL-1的GLPP均抑制了Rh-123的外排,其外排分别降低了8％、16％、19％、33％,具有浓度依赖性.高、中浓度的GLPP(50、100 μg·mL-1)对Rh-123的双向转运有一定的抑制,外排率(ER)较阴性对照组降低了15％、18％.细胞与药物作用72 h后,细胞抗体荧光强度降低,P-gp的表达降低.结论 GLPP对P-gp的活性有一定的抑制作用,能在较短的时间内增加细胞内Rh-123的蓄积,抑制Rh-123的双向转运.长期使用GLPP可抑制P-gp的表达.     

植物药对MDR1基因的调控及对P-gp功能的影响

P糖蛋白（P-gp）是由人类MDR1基因编码的磷酸糖蛋白,是三磷酸腺苷（ATP）转运蛋白超家族成员之一,具有ATP依赖性的药物外排泵功能。定向诱变研究显示,P-gp各处都分布着药物结合位点,甚至是ATP结合区域。P—gp在肝、肾、胰腺、小肠、结肠、肾上腺的上皮细胞及血脑屏障表面高度表达,在药物的吸收、分布、排泄过程中发挥着重要作用。     

Labrasol对肠P-糖蛋白功能的影响

目的　研究Labrasol对肠P -糖蛋白功能的影响。方法　用大鼠的离体肠段,通过体外Ussingchamber的转运实验,研究了Labrasol对P -糖蛋白底物若丹明1 2 3转运的影响,同时考察了非P -糖蛋白底物荧光黄在Labrasol作用下的转运行为。结果　低浓度(0 .0 5 %～0 .0 75 %)的Labrasol能够抑制回肠与结肠中P -糖蛋白的功能。同时,对荧光黄的转运无显著影响。结论　Labrasol有望作为P -糖蛋白抑制剂,用于改善受P -糖蛋白介导药物的吸收,提高口服药物的生物利用度。     

Strategies for therapy of retinal diseases using systemic drug delivery: relevance of transporters at the blood-retinal barrier

INTRODUCTION: There is an increasing need for managing rapidly progressing retinal diseases because of the potential loss of vision. Although systemic drug administration is one possible route for treating retinal diseases, retinal transfer of therapeutic drugs from the circulating blood is strictly regulated by the blood-retinal barrier (BRB). AREAS COVERED: This review discusses the constraints and challenges of drug delivery to the retina. In addition, this article discusses the properties of drugs and the conditions of the BRB that affect drug permeability. The reader will gain insights into the strategies for developing therapeutic drugs that are able to cross the BRB for treating retinal diseases. Further, the reader will gain insights into the role of BRB physiology including barrier functions, and the effect of influx and efflux transporters on retinal drug delivery. EXPERT OPINION: When designing and selecting optimal drug candidates, it's important to consider the fact that they should be recognized by influx transporters and that efflux transporters at the BRB should be avoided. Although lipophilic cationic drugs are known to be transported to the brain across the blood-brain barrier, verapamil transport to the retina is substantially higher than to the brain. Therefore, lipophilic cationic drugs do have a great ability to increase influx transport across the BRB.     

Current strategies for targeted delivery of bio-active drug molecules in the treatment of brain tumor

Brain tumor is one of the most challenging diseases to treat. The major obstacle in the specific drug delivery to brain is blood–brain barrier (BBB). Mostly available anti-cancer drugs are large hydrophobic molecules which have limited permeability via BBB. Therefore, it is clear that the protective barriers confining the passage of the foreign particles into the brain are the main impediment for the brain drug delivery. Hence, the major challenge in drug development and delivery for the neurological diseases is to design non-invasive nanocarrier systems that can assist controlled and targeted drug delivery to the specific regions of the brain. In this review article, our major focus to treat brain tumor by study numerous strategies includes intracerebral implants, BBB disruption, intraventricular infusion, convection-enhanced delivery, intra-arterial drug delivery, intrathecal drug delivery, injection, catheters, pumps, microdialysis, RNA interference, antisense therapy, gene therapy, monoclonal/cationic antibodies conjugate, endogenous transporters, lipophilic analogues, prodrugs, efflux transporters, direct conjugation of antitumor drugs, direct targeting of liposomes, nanoparticles, solid–lipid nanoparticles, polymeric micelles, dendrimers and albumin-based drug carriers.     

Strategies for therapy of retinal diseases using systemic drug delivery: relevance of transporters at the blood–retinal barrier

Introduction: There is an increasing need for managing rapidly progressing retinal diseases because of the potential loss of vision. Although systemic drug administration is one possible route for treating retinal diseases, retinal transfer of therapeutic drugs from the circulating blood is strictly regulated by the blood–retinal barrier (BRB).

Areas covered: This review discusses the constraints and challenges of drug delivery to the retina. In addition, this article discusses the properties of drugs and the conditions of the BRB that affect drug permeability. The reader will gain insights into the strategies for developing therapeutic drugs that are able to cross the BRB for treating retinal diseases. Further, the reader will gain insights into the role of BRB physiology including barrier functions, and the effect of influx and efflux transporters on retinal drug delivery.

Expert opinion: When designing and selecting optimal drug candidates, it's important to consider the fact that they should be recognized by influx transporters and that efflux transporters at the BRB should be avoided. Although lipophilic cationic drugs are known to be transported to the brain across the blood–brain barrier, verapamil transport to the retina is substantially higher than to the brain. Therefore, lipophilic cationic drugs do have a great ability to increase influx transport across the BRB.     

Strategies for increasing drug delivery to the brain: focus on brain lymphoma

The blood-brain barrier (BBB) is a gate that controls the influx and efflux of a wide variety of substances and consequently restricts the delivery of drugs into the central nervous system (CNS). Brain tumours may disrupt the function of this barrier locally and nonhomogeneously. Therefore, the delivery of drugs to brain tumours has long been a controversial subject. The current concept is that inadequate drug delivery is a major factor that explains the unsatisfactory response of chemosensitive brain tumours. Various strategies have been devised to circumvent the BBB in order to increase drug delivery to the CNS. The various approaches can be categorised as those that attempt to increase delivery of intravascularly administered drugs, and those that attempt to increase delivery by local drug administration. Strategies that increase delivery of intravascularly injected drugs can manipulate either the drugs or the capillary permeability of the various barriers (BBB or blood-tumour barrier), or may attempt to increase plasma concentration or the fraction of the drug reaching the tumour (high-dose chemotherapy, intra-arterial injection). Neurotoxicity is a major concern with increased penetration of drugs into the CNS or when local delivery is practised. Systemic toxicity remains the limiting factor for most methods that use intravascular delivery. This review evaluates the strategies used to increase drug delivery in view of current knowledge of drug pharmacokinetics and its relevance to clinical studies of chemosensitive brain tumours. The main focus is on primary CNS lymphoma, as it is a chemosensitive brain tumour and its management routinely utilises specialised strategies to enhance drug delivery to the affected CNS compartments.     

Pulmonary absorption rate and bioavailability of drugs in vivo in rats: structure-absorption relationships and physicochemical profiling of inhaled drugs

The aim of this investigation was to analyze the structure-absorption relationships for pulmonary delivered drugs. First, the inhaled drugs on the market during 2001 were identified and a profile of the calculated physicochemical properties was made. Second, an in vivo pharmacokinetic investigation was performed in anesthetized rats. Eight selected drugs were administered by intratracheal nebulization and intravenous bolus administration and the plasma concentrations of the drugs were determined by LC-MS-MS. Third, an evaluation of the relationships between the absorption/bioavailability data and the drugs' physicochemical characteristics and the epithelial permeability in Caco-2 cells, respectively, was performed. The drug absorption rate was found to correlate to the molecular polar surface area and the hydrogen bonding potential, as well as to the apparent permeability in Caco-2 cell monolayers, which indicated that passive diffusion was the predominating mechanism of absorption in the rat lung. In contrast to the intestinal mucosa and the blood-brain barrier, the pulmonary epithelium was shown to be highly permeable to compounds with high molecular polar surface area (e.g., PSA 479 A(2)). Furthermore, a high bioavailability was found for the efflux transporter substrates talinolol (81%) and losartan (92%), which provides functional evidence for a quantitatively less important role for efflux transporters, such as P-glycoprotein, in limiting the absorption of these drugs from the rat lung. In conclusion, the pulmonary route should be regarded as a potential alternative for the delivery of drugs that are inadequately absorbed after oral administration.     

Absorption of poorly water soluble drugs subject to apical efflux using phospholipids as solubilizers in the Caco-2 cell model.

The purpose of this work was to determine the influence of liposomal solubilization of poorly water soluble drugs exhibiting apical efflux on permeation kinetics and cell toxicity in Caco-2 cells. The HIV-protease inhibitors indinavir and saquinavir were incorporated in phosphatidylcholine liposomes at maximal drug-to-lipid mass ratios and their absorption was determined in Caco-2 cell cultures grown on Transwell inserts using purely aqueous drug solutions as reference. A novel mathematical model was developed to quantitatively delineate the contribution of passive membrane permeation and carrier mediated efflux to transport across the cell monolayer and passive permeability coefficient and maximal efflux rate and affinity constant of the transporter system were determined. Cell toxicity of phospholipids was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and the lactate dehydrogenase (LDH) assay. Cell integrity was not significantly affected by phospholipid concentrations of up to 150 mg/ml with respect to the used standard tests. Maximum drug concentration was increased 10- and 750-fold for indinavir and saquinavir, respectively, by the use of liposomes. The passive membrane permeability coefficient differed between the two drugs in accordance with their lipophilicity and the affinity for apical efflux transporters was on average 4-fold greater for saquinavir than for indinavir. Liposomal solubilization diminished the passive permeability coefficient of both drugs but the passive apical-to-basal delivery rate was increased by the liposomes compared to the purely aqueous solutions at maximal donor concentrations for at least one of the two drugs. Efflux rate reached a maximum for the liposomal formulations reflecting transporter saturation. Hence, liposomal solubilization considerably increased drug concentration in the media and altered absorption behavior by affecting both the passive diffusion and the carrier mediated efflux components of cell monolayer permeation.     

On The Rate and Extent of Drug Delivery to the Brain

To define and differentiate relevant aspects of blood-brain barrier transport and distribution in order to aid research methodology in brain drug delivery. Pharmacokinetic parameters relative to the rate and extent of brain drug delivery are described and illustrated with relevant data, with special emphasis on the unbound, pharmacologically active drug molecule. Drug delivery to the brain can be comprehensively described using three parameters: Kp,uu (concentration ratio of unbound drug in brain to blood), CLin (permeability clearance into the brain), and Vu,brain (intra-brain distribution). The permeability of the blood-brain barrier is less relevant to drug action within the CNS than the extent of drug delivery, as most drugs are administered on a continuous (repeated) basis. Kp,uu can differ between CNS-active drugs by a factor of up to 150-fold. This range is much smaller than that for log BB ratios (Kp), which can differ by up to at least 2,000-fold, or for BBB permeabilities, which span an even larger range (up to at least 20,000-fold difference). Methods that measure the three parameters Kp,uu, CLin, and Vu,brain can give clinically valuable estimates of brain drug delivery in early drug discovery programmes.     

A comprehensive account on the role of efflux transporters in the gastrointestinal absorption of 13 commonly used substrate drugs in humans

BACKGROUND: The potential absorption-limiting effect of intestinal efflux transporters such as P-glycoprotein (P-gp) has been well recognized, primarily based on results of numerous Caco-2 cell studies showing that flux, permeability, or transport clearance of drugs from the basolateral to the apical (B --> A) compartment is greater than that from the apical to the basolateral (A --> B) compartment. Except for very limited examples such as celiprolol, talinolol, pafenolol and paclitaxel, the potential clinical impact of these transporters on oral absorption of the vast number of commonly prescribed drug substrates in humans has not been closely examined to date. OBJECTIVE: To evaluate whether these efflux transporters may play a significant role in limiting oral absorption of 13 commonly used drugs (digoxin, etoposide, felodipine, fexofenadine, furosemide, indinavir, losartan, nadolol, propranolol, ritonavir, saquinavir, tacrolimus, and verapamil) in humans. METHODS: Drug absorption properties such as the rate (as judged by the Cmax and tmax) and extent (as judged by AUC or urinary excretion of drugs) of absorption as a function of dose, as well as the completeness of oral absorption were obtained from the literature. RESULTS: The absorption properties of these 13 drugs are not consistent with absorption-retarding expectations from in vitro studies because they all show apparent dose-independent kinetics in absorption or bioavailability and completeness of oral absorption is shown for most of the drugs evaluated. CONCLUSIONS: In spite of being substrates of intestinal efflux transporters such as P-gp, the in vivo oral absorption of 13 drugs examined apparently is not significantly impeded by efflux transporters. Thus, there may exist an apparent discrepancy between in vitro "expectations" and in vivo results; potential reasons for this are discussed. The present findings, however, do not de-emphasize potential in vivo importance of efflux transporters in affecting (increasing or decreasing) oral absorption of certain substrate drugs, especially those with low to moderate intestinal permeability and with low therapeutic index, or the importance of efflux transporters in the study of mechanisms of drug absorption and some potentially clinically significant drug-drug and drug-food interactions.     

Transporter-mediated permeation of drugs across the blood-brain barrier

Drug distribution into the brain is strictly regulated by the presence of the blood-brain barrier (BBB) that is formed by brain capillary endothelial cells. Since the endothelial cells are connected to each other by tight junctions and lack pores and/or fenestrations, compounds must cross the membranes of the cells to enter the brain from the bloodstream. Therefore, hydrophilic compounds cannot cross the barrier in the absence of specific mechanisms such as membrane transporters or endocytosis. So, for efficient supply of hydrophilic nutrients, the BBB is equipped with membrane transport systems and some of those transporter proteins have been shown to accept drug molecules and transport them into brain. In the present review, we describe mainly the transporters that are involved in drug transfer across the BBB and have been molecularly identified. The transport systems described include transporters for amino acids, monocarboxylic acids, organic cations, hexoses, nucleosides, and peptides. Most of these transporters function in the direction of influx from blood to brain; the presence of efflux transporters from brain to blood has also been demonstrated, including P-glycoprotein, MRPs, and other unknown transporters. These efflux transporters seem to be functional for detoxication and/or prevention of nonessential compounds from entering the brain. Various drugs are transported out of the brain via such efflux transporters, resulting in the decrease of CNS side effects for drugs that have pharmacological targets in peripheral tissues or in the reduction of efficacy in CNS because of the lower delivery by efflux transport. To identify the transporters functional at the BBB and to examine the possible involvement of them in drug transports by molecular and physiological approaches will provide a rational basis for controlling drug distribution to the brain.