转运体在药物排泄中的作用及在新药研发中的意义

本文介绍了药物转运体在药物排泄过程中的作用,探讨了其在新药研发和临床应用中的可能性。通过对药物转运体功能的了解和利用,可以开发出对某些器官有靶向性的药物,或避免药物分布到某些器官中,从而提高药物的疗效,降低其毒副作用;也可以通过对转运体介导的药物相互作用及肝肠循环的研究,指导临床更加安全有效的用药。在药物研发的初始阶段,就开始重视其药动学特性,这一观念近年来已被很多人所接受。对药物转运体的深入认识和利用,建立高通量的药物转运体筛选体系,对于加速新药研发的进程将具有极其重要的意义。     

Impact of drug transporter studies on drug discovery and development

Drug transporters are expressed in many tissues such as the intestine, liver, kidney, and brain, and play key roles in drug absorption, distribution, and excretion. The information on the functional characteristics of drug transporters provides important information to allow improvements in drug delivery or drug design by targeting specific transporter proteins. In this article we summarize the significant role played by drug transporters in drug disposition, focusing particularly on their potential use during the drug discovery and development process. The use of transporter function offers the possibility of delivering a drug to the target organ, avoiding distribution to other organs (thereby reducing the chance of toxic side effects), controlling the elimination process, and/or improving oral bioavailability. It is useful to select a lead compound that may or may not interact with transporters, depending on whether such an interaction is desirable. The expression system of transporters is an efficient tool for screening the activity of individual transport processes. The changes in pharmacokinetics due to genetic polymorphisms and drug-drug interactions involving transporters can often have a direct and adverse effect on the therapeutic safety and efficacy of many important drugs. To obtain detailed information about these interindividual differences, the contribution made by transporters to drug absorption, distribution, and excretion needs to be taken into account throughout the drug discovery and development process.     

靶向给药研究的新进展

靶向给药可使治疗部位的药物浓度明显提高, 可减少用药量并使治疗费用降低, 降低药物对全身的毒副作用。因此, 靶向给药是目前研究的热点, 本文综述了近年来靶向给药的相关研究, 主要从被动靶向、主动靶向以及物理化学靶向3个方面阐述了靶向给药的研究进展。     

Membrane transporter/receptor-targeted prodrug design: strategies for human and veterinary drug development

The bioavailability of drugs is often severely limited due to the presence of biological barriers in the form of epithelial tight junctions, efflux proteins and enzymatic degradation. Physicochemical properties, such as lipophilicity, molecular weight, charge, etc., also play key roles in determining the permeation properties of drug candidates. As a result, many potential drug candidates may be dropped from the initial screening portfolio. Prodrug derivatization targeting transporters and receptors expressed on mammalian cells holds tremendous potential. Enhanced cellular delivery can significantly improve drug absorption. Such approaches of drug targeting and delivery have been the subject of intense research. Various prodrugs have been designed that demonstrate enhanced bioavailability and tissue specificity. This approach is equally applicable to human and veterinary pharmaceuticals since most of the transporters and receptors expressed by human tissues are also expressed in animals. This review highlights studies conducted on the use of transporters and receptors in an effort to improve drug bioavailability and to develop targeted drug delivery systems.     

Targeted prodrug design to optimize drug delivery

Classical prodrug design often represents a nonspecific chemical approach to mask undesirable drug properties such as limited bioavailability, lack of site specificity, and chemical instability. On the other hand, targeted prodrug design represents a new strategy for directed and efficient drug delivery. Particularly, targeting the prodrugs to a specific enzyme or a specific membrane transporter, or both, has potential as a selective drug delivery system in cancer chemotherapy or as an efficient oral drug delivery system. Site-selective targeting with prodrugs can be further enhanced by the simultaneous use of gene delivery to express the requisite enzymes or transporters. This review highlights evolving strategies in targeted prodrug design, including antibody-directed enzyme prodrug therapy, genedirected enzyme prodrug therapy, and peptide transporter-associated prodrug therapy.     

联合用药的药物相互作用及研究方法

随着人们对于疾病的认识越来越深入,联合用药得到越来越普遍的使用,同时所产生的药物间的相互作用也越来越受到关注。联合用药可能通过影响与药物吸收、分布、代谢、排泄等相关的酶、转运体等,以改变药物的药代属性（生物利用度、分布特性等）,调节体内动态药效物质组的构成,改变药物的药效（协同作用、拮抗作用、毒副作用等）,从而对药物的有效性、安全性产生影响。从联合用药对药物吸收与代谢的影响这两方面来阐述联合用药的研究近况,为联合用药的基础研究以及临床应用的安全有效提供参考。     

Brain drug targeting and gene technologies.

Brain drug targeting technology is based on the application of four gene technologies that enable the delivery of drugs or genes across the blood-brain barrier (BBB) in vivo. I) Genetic engineering is used to produce humanized monoclonal antibodies that target endogenous BBB transporters and act as vectors for delivery of drugs or genes to the human brain. The conjugate of a neurotherapeutic and a BBB transport vector is called a chimeric peptide. Epidermal growth factor chimeric peptides have been used for neuroimaging of brain cancer. Brain-derived neutrophic factor chimeric peptides have marked neuroprotective effects in brain stroke models. II) Imaging gene expression in the brain in vivo is possible with sequence-specific antisense radiopharmaceuticals, which are conjugated to BBB drug targeting vectors. III) Brain gene targeting technology enables widespread expression of an exogenous gene throughout the central nervous system following an intravenous injection of a non-viral therapeutic gene. IV) A BBB genomics program enables the future discovery of novel transport systems expressed at the BBB. These transporters may be carrier-mediated transport systems, active efflux transporters, or receptor-mediated transcytosis systems. The future discovery of novel BBB transport systems and the application of brain drug targeting technology will enable the delivery to the brain of virtually any neurotherapeutic, including small molecules, large molecules and gene medicines.     

DNA甲基化在药物效应和新药研发中的研究进展

DNA甲基化对药物作用的影响日渐受到关注。许多编码药物代谢酶、药物转运体、核受体及药物靶点的基因受DNA甲基化调控。DNA甲基化在影响细胞色素P450酶(CYP450)的表达水平上起着重要的作用,而CYP450酶系催化多种药物代谢反应,能显著影响药物疗效。目前的研究也发现DNA甲基化水平在个体间的差异与药物疗效和不良反应在个体间的差异是紧密相关的。DNA甲基化状态会受药物作用影响,进而引起不同程度的药物不良反应。近年来,以DNA甲基化为靶向的药物研发呈增长态势,DNA甲基转移酶抑制剂对肿瘤等重大疾病治疗具决定性作用。临床试验结果显示,DNA甲基化药物治疗已在改善药物疗效、稳定药理作用及减少药物不良反应上初见成效。DNA甲基化可能成为早期预测药物效应的潜在生物标记,将成为实现临床个体化用药的有力工具。     

Future directions for drug transporter modelling

Since the late 1980s computational methods such as quantitative structure-activity relationship (QSAR) and pharmacophore approaches have become more widely applied to assess interactions between drug-like molecules and transporters, starting with P-glycoprotein (P-gp). Identifying molecules that interact with P-gp and other transporters is important for drug discovery, but it is normally ascertained using laborious in vitro and in vivo studies. Computational QSAR and pharmacophore models can be used to screen commercial databases of molecules rapidly and suggest those likely to bind as substrates or inhibitors for transporters. These predictions can then be readily verified in vitro, thus representing a more efficient route to screening. Recently, the application of this approach has seen the identification of new substrates and inhibitors for several transporters. The successful application of computational models and pharmacophore models in particular to predict transporter binding accurately represents a way to anticipate drug-drug interactions of novel molecules from molecular structure. These models may also see incorporation in future pharmacokinetic-pharmacodynamic models to improve predictions of in vivo drug effects in patients. The implications of early assessment of transporter activity, current advances in QSAR, and other computational methods for future development of these and systems-based approaches will be discussed.     

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。     

Multidrug transporters as drug targets

Transport molecules can significantly affect the pharmacodynamics and pharmacokinetics of drugs. An important transport molecule, the 170 kDa P-glycoprotein (Pgp), is constitutively expressed at several organ sites in the human body. Pgp is expressed at the blood-brain barrier, in the kidneys, liver, intestines and in certain T cells. Other transporters such as the multidrug resistance protein 1 (MRP1) and MRP2 also contribute to drug distribution in the human body, although to a lesser extent than Pgp. These three transporters, and especially Pgp, are often targets of drugs. Pgp can be an intentional or unintentional target. It is directly targeted when one wants to block its function by a modifier drug so that another drug, also a substrate of Pgp, can penetrate the cell membrane, which would otherwise be impermeable. Unintentional targeting occurs when several drugs are administered to a patient and as a consequence, the physiological function of Pgp is blocked at different organ sites. Like Pgp, MRP1 also has the capacity to mediate transport of many drugs and other compounds. MRP1 has a protective role in preventing accumulation of toxic compounds and drugs in epithelial tissue covering the choroid plexus/cerebrospinal fluid compartment, oral epithelium, sertoli cells, intesticular tubules and urinary collecting duct cells. MRP2 primarily transports weakly basic drugs and bilirubin from the liver to bile. Most compounds that efficiently block Pgp have only low affinity for MRP1 and MRP2. There are only a few effective and specific MRP inhibitors available. Drug targeting of these transporters may play a role in cancer chemotherapy and in the pharmacokinetics of substrate drugs.     

A regulatory viewpoint on transporter-based drug interactions

1. Pharmacokinetic drug interactions can lead to serious adverse events and the evaluation of a new molecular entity's (NME) drug-drug interaction potential is an integral part of drug development and regulatory review before its market approval. Clinically relevant interactions mediated by transporters are of increasing interest in clinical development and research in this emerging area and it has been revealed that drug transporters can play an important role in modulating drug absorption, distribution, metabolism and elimination. 2. Acting alone or in concert with drug-metabolizing enzymes transporters can affect the pharmacokinetics and/or pharmacodynamics of a drug. The newly released drug interaction guidance by the US Food and Drug Administration (USFDA) includes new information addressing drug transporter interactions with a primary focus on P-glycoprotein (P-gp, ABCB1). 3. This paper provides a regulatory viewpoint on transporters and their potential role in drug-drug interactions. It first outlines information that might be needed during drug development and ultimately included in new drug application (NDA) submissions to address potential transporter-mediated drug interactions. Next, it explains criteria that may warrant conduct of in vivo P-gp-mediated drug interaction studies based on in vitro assessment. In addition, it includes a review case that describes the evaluation of data suggesting a P-gp-based induction interaction.     

磁性药物载体在抗肿瘤方面的研究进展

通过外加磁场的引导作用,使负载抗癌药物的磁性载体靶向定位于靶区,提高靶组织的药物浓度,有效降低药物对正常组织或细胞的毒副作用及其他不良反应。磁性药物载体还具有靶向性、缓释、控释等优点,已成为了肿瘤靶向治疗常用的新型载体系统。本文综述了磁性药物载体磁性纳米颗粒、磁性脂质体、磁性微球在肿瘤治疗与诊断中的应用进展。     

Targeting intestinal transporters for optimizing oral drug absorption

While the oral exposure continues to be the major focus, the chemical space of recent drug discovery is apparently trending towards more hydrophilic libraries, due to toxicity and drug-interactions issues usually reported with lipophilic drugs. This trend may bring in challenges in optimizing the membrane permeability and thus the oral absorption of new chemical entities. It is now apparent that the influx transporters such as peptide transporter 1 (PepT1), organic-anion transporting polypeptides (OATPs), monocarboxylate transporters (MCT1) facilitate, while efflux pumps (e.g. P-glycoprotein (P-gp), breast cancer resistance protein (BCRP)) limit oral absorption of drugs. This review will focus on intestinal transporters that may be targeted to achieve optimal clinical oral plasma exposure for hydrophilic and polar drugs. The structure, mechanism, structure-activity relationships and the clinical examples on the functional role of these transporters in the drug absorption was discussed. Physicochemical properties, lipophilicity and hydrogen-bonding ability, show good correlation with transport activity for efflux pumps. Although several attempts were made to describe the structural requirements based on pharmacophore modeling, lack of crystal structure of transporters impeded identification of definite properties for transporter affinity and favorable transport activity. Furthermore, very few substrate drug datasets are currently available for the influx transporters to derive any clear relationships. Unfortunately, gaps also exist in the translation of in vitro end points to the clinical relevance of the transporter(s) involved. However, it may be qualitatively generalized that targeting intestinal transporters are relevant for drugs with high solubility and/or low passive permeability i.e. a class of compounds identified as Class III and Class IV according to the Biopharmaceutic Classification System (BCS) and the Biopharmaceutic Drug Disposition Classification System (BDDCS). A careful considerations to oral dose based on the transporter clearance (V(max)/K(m)) capacity is needed in targeting a particular transporter. For example, low affinity and high capacity uptake transporters such as PEPT1 and MCT1 may be targeted for high oral dose drugs.     

Model-based optimized steering and focusing of local magnetic particle concentrations for targeted drug delivery

Magnetic drug targeting (MDT) is an application in the field of targeted drug delivery in which magnetic (nano)particles act as drug carriers. The particles can be steered toward specific regions in the human body by adapting the currents of external (electro)magnets. Accurate models of particle movement and control algorithms for the electromagnet currents are two of the many requirements to ensure effective drug targeting. In this work, a control approach for the currents is presented, based on an underlying physical model that describes the dynamics of particles in a liquid in terms of their concentration in each point in space. Using this model, the control algorithm determines the currents generating the magnetic fields that maximize the particle concentration in spots of interest over a period of time. Such an approach is computationally only feasible thanks to our innovative combination of model order reduction with the method of direct multiple shooting. Simulation results of an in-vitro targeting setup demonstrated that a particle collection can be successfully guided toward the targeted spot with limited dispersion through a surrounding liquid. As now present and future particle behavior can be taken into account, and non-stationary surrounding liquids can be dealt with, a more precise and flexible targeting is achieved compared to existing MDT methods. This proves that the presented methodology can bring MDT closer to its clinical application. Moreover, the developed model is compatible with state-of-the-art imaging methods, paving the way for theranostic platforms that combine both therapy as well as diagnostics.     

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.     

A regulatory viewpoint on transporter-based drug interactions

1.?Pharmacokinetic drug interactions can lead to serious adverse events and the evaluation of a new molecular entity's (NME) drug–drug interaction potential is an integral part of drug development and regulatory review before its market approval. Clinically relevant interactions mediated by transporters are of increasing interest in clinical development and research in this emerging area and it has been revealed that drug transporters can play an important role in modulating drug absorption, distribution, metabolism and elimination.

2.?Acting alone or in concert with drug-metabolizing enzymes transporters can affect the pharmacokinetics and/or pharmacodynamics of a drug. The newly released drug interaction guidance by the US Food and Drug Administration (USFDA) includes new information addressing drug transporter interactions with a primary focus on P-glycoprotein (P-gp, ABCB1).

3.?This paper provides a regulatory viewpoint on transporters and their potential role in drug–drug interactions. It first outlines information that might be needed during drug development and ultimately included in new drug application (NDA) submissions to address potential transporter-mediated drug interactions. Next, it explains criteria that may warrant conduct of in vivo P-gp-mediated drug interaction studies based on in vitro assessment. In addition, it includes a review case that describes the evaluation of data suggesting a P-gp-based induction interaction.     

Genomics and cancer drug resistance

Cellular drug resistance is a major obstacle in cancer therapy. Mechanisms of resistance can be associated with altered expression of ATP-binding cassette (ABC) family of transporters on cell membrane transporters, the most common cause of multi-drug resistance (MDR), but can also include alterations of DNA repair pathways, resistance to apoptosis and target modifications. Anti-cancer treatments may be divided into different categories based on their purpose and action: chemotherapeutic agents damage and kill dividing cells; hormonal treatments prevent cancer cells from receiving signals essential for their growth; targeted drugs are a relatively new cancer treatment that targets specific proteins and pathways that are limited primarily to cancer cells or that are much more prevalent in cancer cells; and antibodies function by either depriving the cancer cells of necessary signals or by causing their direct death. In any case, resistance to anticancer therapies leads to poor prognosis of patients. Thus, identification of novel molecular targets is critical in development of new, efficient and specific cancer drugs. The aim of this review is to describe the impact of genomics in studying some of the most critical pathways involved in cancer drug resistance and in improving drug development. We shall also focus on the emerging role of microRNAs, as key gene expression regulators, in drug resistance. Finally, we shall address the specific mechanisms involved in resistance to tyrosine kinase inhibitors in chronic myeloid leukemia.     

Scientific perspectives on drug transporters and their role in drug interactions

Recently, increased interest in drug transporters and research in this area has revealed that drug transporters play an important role in modulating drug absorption, distribution, and elimination. Acting alone or in concert with drug metabolizing enzymes they can affect the pharmacokinetics and pharmacodynamics of a drug. This commentary will focus on the potential role that drug transporters may play in drug-drug interactions and what information may be needed during drug development and new drug application (NDA) submissions to address potential drug interactions mediated by transporters.     

Brain tumor-targeted drug delivery strategies

Despite the application of aggressive surgery, radiotherapy and chemotherapy in clinics, brain tumors are still a difficult health challenge due to their fast development and poor prognosis. Brain tumor-targeted drug delivery systems, which increase drug accumulation in the tumor region and reduce toxicity in normal brain and peripheral tissue, are a promising new approach to brain tumor treatments. Since brain tumors exhibit many distinctive characteristics relative to tumors growing in peripheral tissues, potential targets based on continuously changing vascular characteristics and the microenvironment can be utilized to facilitate effective brain tumor-targeted drug delivery. In this review, we briefly describe the physiological characteristics of brain tumors, including blood–brain/brain tumor barriers, the tumor microenvironment, and tumor stem cells. We also review targeted delivery strategies and introduce a systematic targeted drug delivery strategy to overcome the challenges.Key words: Barriers targeting, Tumor microenvironment, Tumor cells, Systematic targeted drug delivery