核苷类抗病毒药群体药动学研究及应用

群体药动学运用经典药动学统计学相结合的方法来定量考察目标群体中药物浓度的影响因素,并应用于优化临床药物治疗方案。核苷类抗病毒药在临床抗病毒治疗中发挥重要的作用,此类药物的疗效、不良反应与其体内药物浓度息息相关,阿昔洛韦、更昔洛韦、泛昔洛韦、齐多夫定、恩曲他滨、拉米夫定和阿巴卡韦等核苷类抗病毒药的群体药动学研究促进该类药物在临床的合理应用。     

碳环核苷类化合物的研究概况

核苷类的抗肿瘤药和抗病毒药,虽已广泛应用于临床,但随着近年来广谱高效抗病毒药的开发,核苷类药物的研究仍不失为寻找有效药物的一个重要方面。鉴于核苷类化合物结构上的特点,在体内代谢过程中其苷键易被各种酶水解而影响其治疗作用,此外有些核苷药物如阿糖腺苷和阿糖胞苷的碱基中的氨基在体内易受脱氨酶的作用,脱氨生成无活性的阿糖肌苷和阿糖脲苷。因     

疾病状态下有机阴离子转运体表达和功能的变化及其机制研究进展

有机阴离子转运体属于溶质转运体22亚家族成员，是一类重要的摄取类转运体，其有多个亚型。有机阴离子转运体在体内介导多种小分子内源性物质的转运，起到维持机体内环境稳态的作用。此外，临床上许多药物也是有机阴离子转运体的底物。研究表明某些疾病可能导致有机阴离子转运体表达和功能的异常改变，进而影响药物的疗效或导致机体内源性物质水平紊乱。对有机阴离子转运体的分布和功能进行简要介绍，并综述了疾病状态下有机阴离子转运体表达和功能变化及其机制的研究进展。     

2007 年至 2011 年我院门诊核苷类抗病毒药应用简

目的调查医院门诊核苷类抗病毒药的应用情况,分析其发展趋势,为临床合理用药提供参考。方法对医院门诊核苷类抗病毒药的销售数量、金额、用药频度（DDDs）、日均费用（DDC）等进行统计、分析。结果核苷类抗病毒药的销售数量、金额、DDDs均呈逐年增长趋势。结论医院核苷类抗病毒药应用基本合理,符合用药特点,但用药时应关注不良反应的发生,使用药更加安全、有效、经济、合理。     

肾脏转运体和/或代谢酶介导药物排泄及药物相互作用的研究进展

肾脏是人体最重要的排泄器官。肾单元近端小管细胞具有多种药物转运体和代谢酶,在药物及其代谢物处置中发挥关键作用。近端小管细胞中主要转运体包括有机阴离子转运体、有机阳离子转运体、有机阳离子/肉毒碱转运体、多药及毒素外排转运蛋白、P-糖蛋白、乳腺癌耐药蛋白和多药耐药相关蛋白;主要代谢酶包括细胞色素P450酶,UDP-葡萄糖醛酸基转移酶、磺酸基转移酶、谷胱甘肽S-转移酶。肾脏转运体和/或代谢酶介导药物相互作用(DDIs)是临床关注的重要问题。肾脏转运体和代谢酶存在密切协作关系,在肾脏也存在多种相互作用现象(包括转运-转运相互作用,代谢-代谢相互作用和转运-代谢相互作用),其显著影响药物肾脏处置、临床疗效和肾毒性。本文系统阐述了这些相互作用对药物及其代谢物的肾脏排泄、药动学、DDIs和肾毒性的影响。今后需要进一步阐明肾脏转运-代谢相互作用机制,将有助于研究体内药物肾脏处置和DDIs,促进临床合理用药。     

PDZK1蛋白对药物转运体的调控

PDZK1蛋白通过PDZ结构域与药物转运体结合,显示对药物转运体定位、表达及功能的调控作用。药物转运体介导了众多内源和外源性物质,如营养物质、治疗药物等的跨膜转运,是肿瘤多药耐药及多种疾病发生的关键因素,且在治疗药物的体内处置中具有重要地位。PDZK1蛋白对药物转运体的调控间接影响上述过程。本文就PDZK1对药物转运体的调控作用研究进行综述。     

转运体介导中药与化学药相互作用研究进展

ATP结合盒转运体家族和溶质转运体家族的转运体参与众多的中药与化学药相互作用过程,因其可介导内外源性药物及其代谢物的跨膜转运。转运体同细胞色素P450酶类似,会对特征底物的血药浓度和组织分布产生一定影响,从而改变药物的药效或者毒副作用。本文综述了具有重要临床意义的P-糖蛋白、乳腺癌耐药蛋白、有机阴离子转运体、有机阳离子转运体和有机阴离子转运多肽等5种转运体所介导的中药与化学药相互作用,以期为临床联合用药提供一定的理论依据。     

肾脏中转运体对核苷类抗病毒药物的转运作用

药物转运体在药物的药动学和药效学过程中发挥重要作用,而核苷类抗病毒药物与其他药物的相互作用主要基于肾小管膜上表达的转运体。本论文分别对肾脏中参与核苷类抗病毒药物转运的转运体,几种主要核苷类抗病毒药物以及它们之间相互作用的研究现状进行了综述。     

2008—2010年上海市27家医院应用核苷类抗病毒药治疗乙型肝炎情况分析

目的:了解2008—2010年上海市核苷类抗病毒药应用情况及用药趋势,为临床合理应用提供参考。方法:采用销售金额排序法、限定日剂量(DDD)法、用药频度(DDDs)排序法、取药量/处方数比值法,对2008—2010年上海市27家样本医院临床使用的核苷类抗病毒药数据进行回顾性统计分析。结果:使用核苷类抗病毒药的乙型肝炎患者中,以≥45岁的中老年人为主,门诊男女患者比例为1.93∶1,住院男女患者比例为3.81∶1;各种核苷类抗病毒药的使用呈现较大差异,恩替卡韦占据了50%以上市场份额。结论:2008—2010年上海市27家医院核苷类抗病毒药销售品种和数量均呈增长趋势,但个别品种处方超量现象较为普遍,需规范该类药的使用,特别需要控制患者用药的限定日费用(DDC)和取药量/处方数比值。     

药物转运体介导的中药及单体药物相互作用的研究进展

药物转运体在中药及单体成分的体内吸收、分布和排泄过程中发挥着重要的作用。中药及单体对药物转运体的功能和表达可产生诱导或抑制作用,从而影响这些转运体底物的体内处置过程。随着中药药动学的发展,基于转运体介导的中药及单体体内处置研究越来越受到重视。该文对药物转运体介导的中药及单体药动学的研究进行综述。     

Involvement of multiple transporters in the oral absorption of nucleoside analogues

Many nucleoside analogues such as azt, ddI, ddC, d4T, 3TC, acv and vacv are currently being used in the treatment of patients infected with HIV, suffering from AIDS, or AIDS-related opportunistic infections. The transport of nucleoside analogues across the gastrointestinal tract is mediated by a number of transporters that fall into three broad categories, i.e., Na(+)-dependent concentrative transporters, Na(+)-independent equilibrative transporters and H(+)/peptide transporters. The first two transporter classes contain a large number of subtypes that are based on the substrate specificity. Recent studies have shown that most of the anti-HIV nucleoside analogues are transported by one or more of the nucleoside transporters. Furthermore, certain analogues, such as acv, appear to be absorbed by non-carrier-mediated diffusion, whereas vacv is apparently transported by non-nucleoside transporters (e.g., the oligopeptide transporter, PepT1 and possibly others). Thus, it is desirable to understand the precise nature of the absorption mechanism of these drugs to improve bioavailability and reduce the variability that is commonly observed in vivo in human patients. A complete understanding of the complex interactions of nucleoside analogues with the various transporters will help in designing better delivery systems and strategies to improve efficacy. In the current report, the mechanisms of nucleoside and nucleoside-analogue transport are reviewed. Also, methods of exploiting prodrugs to improve the bioavailability characteristics of drugs are highlighted.     

Renal Transport of Adefovir,Cidofovir, and Tenofovir by SLC22A Family Members (hOAT1, hOAT3, and hOCT2)

Purpose The nephrotoxicity of the nucleotide antivirals adefovir, cidofovir and tenofovir is considered to depend on the renal tubular transport of them. Although it is known that the antivirals are substrates of the human renal organic anion transporter hOAT1 (SLC22A6), there is no information available on other organic ion transporters. The aim of the present study was to investigate whether the other renal organic anion transporter hOAT3 (SLC22A8) and organic cation transporter hOCT2 (SLC22A2) transport the antivirals. Materials and Methods Uptake experiments were performed using HEK293 cells transfected with cDNA of the organic ion transporters. Results The uptake of adefovir, cidofovir and tenofovir in monolayers stably expressing hOAT3 increased time-dependently, compared with control. Probenecid, a typical inhibitor of organic anion transporters, completely inhibited their transport. The amounts of the antivirals taken up by hOAT3 were much lower than those by hOAT1. The transient expression of hOCT2 did not increase uptake of the antivirals. Conclusion These results indicate that adefovir, cidofovir and tenofovir are substrates of hOAT3 as well as hOAT1, but that quantitatively hOAT1 is the major renal transporter for these drugs.     

The role of transporters in the toxicity of nucleoside and nucleotide analogs

INTRODUCTION: Two families of nucleoside analogs have been developed to treat viral infections and cancer, but these compounds can cause tissue- and cell-specific toxicity related to their uptake and subcellular activity, which are dictated by host enzymes and transporters. Cellular uptake of these compounds requires nucleoside transporters that share functional similarities but differ in substrate specificity. Tissue-specific cellular expression of these transporters enables nucleoside analogs to produce their tissue-specific toxic effects, a limiting factor in the treatment of retroviruses and cancer. AREAS COVERED: This review discusses the families of nucleoside transporters and how they mediate cellular uptake of nucleoside analogs. Specific focus is placed on examples of known cases of transporter-mediated cellular toxicity and classification of the toxicities resulting. Efflux transporters are also explored as a contributor to analog toxicity and cell-specific effects. EXPERT OPINION: Efforts to modulate transporter uptake/clearance remain long-term goals of oncologists and virologists. Accordingly, subcellular approaches that either increase or decrease intracellular nucleoside analog concentrations are eagerly sought and include transporter inhibitors and targeting transporter expression. However, additional understanding of nucleoside transporter kinetics, tissue expression and genetic polymorphisms is required to design better molecules and better therapies.     

Molecular requirements of the human nucleoside transporters hCNT1, hCNT2, and hENT1

Concentrative nucleoside transporters (CNTs) and equilibrative nucleoside transporters (ENTs) are important in physiological and pharmacological activity and disposition of nucleosides and nucleoside drugs. A better understanding of the structural requirements of inhibitors for these transporters will aid in designing therapeutic agents. To define the relative and unified structural requirements of nucleoside analogs for interaction with hCNT1, hCNT2, and hENT1, we applied an array of structure-activity techniques. Unique pharmacophore models for each respective nucleoside transporter were generated. These models reveal that hCNT2 affinity is dominated by hydrogen bonding features, whereas hCNT1 and hENT1 displayed mainly electrostatic and steric features. Hydrogen bond formation over 3'-OH is essential for all nucleoside transporters. Inhibition of nucleoside transporters by a series of uridine and adenosine analogs and a variety of drugs was analyzed by comparative molecular field analysis. Cross-validated r2 (q2) values were 0.65, 0.52, and 0.74 for hCNT1, hCNT2, and hENT1, respectively. The predictive quality of the models was further validated by successful prediction of the inhibition of a set of test compounds. Addition of a hydroxyl group around the 2-position of purine (or 3-position of pyrimidine) may increase inhibition to hCNT2 transporter; addition of hydroxyl group around the 2,7-position of purine (or the 3,5-position of pyrimidine) would increase the inhibition to hENT1 transporter. Utilization of these models should assist the design of high-affinity nucleoside transporter inhibitors and substrates for both anticancer and antiviral therapy.     

ABC transporters and their role in nucleoside and nucleotide drug resistance

ATP-binding cassette (ABC) transporters confer drug resistance against a wide range of chemotherapeutic agents, including nucleoside and nucleotide based drugs. While nucleoside based drugs have been used for many years in the treatment of solid and hematological malignancies as well as viral and autoimmune diseases, the potential contribution of ABC transporters has only recently been recognized. This neglect is likely because activation of nucleoside derivatives require an initial carrier-mediated uptake step followed by phosphorylation by nucleoside kinases, and defects in uptake or kinase activation were considered the primary mechanisms of nucleoside drug resistance. However, recent studies demonstrate that members of the ABCC transporter subfamily reduce the intracellular concentration of monophosphorylated nucleoside drugs. In addition to the ABCC subfamily members, ABCG2 has been shown to transport nucleoside drugs and nucleoside-monophosphate derivatives of clinically relevant nucleoside drugs such as cytarabine, cladribine, and clofarabine to name a few. This review will discuss ABC transporters and how they interact with other processes affecting the efficacy of nucleoside based drugs.     

Molecular genetics of nucleoside transporters in Leishmania and African trypanosomes

Nucleoside transporters play central roles in the biochemistry of parasitic protozoa such as Leishmania and African trypanosomes, because these parasites cannot synthesize purines de novo and are absolutely reliant upon purine salvage from their hosts. Furthermore, nucleoside transporters are important to the pharmacology of these significant human pathogens, because they mediate the uptake of purine analogs, as well as some non-purine drugs, that are selectively cytotoxic to the parasites. Recent advances in molecular biology and genomics have allowed the cloning and functional expression of several nucleoside transporter genes from Leishmania donovani and Trypanosoma brucei, providing molecular reagents for a detailed functional examination of these permeases and their role in the delivery of nutrients and drugs to the parasites. Furthermore, the molecular basis of drug-resistant mutants that are deficient in nucleoside transport functions can now be fathomed.     

The role of mitochondrial and plasma membrane nucleoside transporters in drug toxicity

Many anticancer and antiviral drugs are nucleoside analogues, which interfere with nucleotide metabolism and DNA replication to produce pharmacological effects. Clinical efficacy and toxicity of nucleoside drugs are closely associated with nucleoside transporters because they mediate the transport of nucleoside drugs across biological membranes. Two families of human nucleoside transporters (equilibrative nucleoside transporters and concentrative nucleoside transporters) have been extensively studied for several decades. They are widely distributed, from the plasma membrane to membranes of organelles such as mitochondria, and the distribution differs in different tissues. In addition, they have different specificities to nucleoside drugs. The characteristics of equilibrative and concentrative nucleoside transporters affect the therapeutic outcomes achieved with anticancer and antiviral nucleoside drugs. In this review, an overview of the role of mitochondrial and plasma membrane nucleoside transporters in nucleoside drug toxicity is provided. Rational design and therapeutic application of nucleoside analogues are also discussed.     

Xenobiotic transporter expression and function in the human mammary gland

Xenobiotic transport in the mammary gland has tremendous clinical, toxicological and nutritional implications. Mechanisms such as passive diffusion, carrier-mediated transport, and transcytosis mediate xenobiotic transfer into milk. In vivo animal and human studies suggest the functional expression of both xenobiotic and nutrient transporters in the lactating mammary gland and the potential involvement of such systems in the significant accumulation of certain compounds in milk. In vitro cell culture systems provide further evidence for carrier-mediated transport across the lactating mammary epithelium. Additionally, molecular characterization studies indicate the expression of various members of the organic cation transporter, organic anion transporter, organic anion polypeptide transporter, oligopeptide transporter, nucleoside and nucleobase transporter, multidrug resistant transporter, and multidrug resistant-like protein transporter families at the lactating mammary epithelium. The in vivo relevance of the expression of such xenobiotic and nutrient transporters and their involvement in drug disposition at the mammary gland requires investigation.     

Role of organic cation transporters in drug-induced toxicity

INTRODUCTION: Membrane transporters are important determinants of in vivo drug disposition, therapeutic efficacy and adverse drug reactions. Many commonly used drugs are organic cations and substrates of organic cation transporters (OCTs). These transporters have a large binding site containing partially overlapping interaction domains for different substrates and are specifically distributed around the body. Consequently, drug interactions with these transporters can result in specific toxicity. AREAS COVERED: This review describes the general properties of OCT and illustrates their importance for the development of important drug toxicities using the examples of metformin and cisplatin. Additionally, this review discusses the role of OCT polymorphisms in the modulation of these toxic effects. EXPERT OPINION: Understanding how drugs interact with membrane transporters is pivotally important in explaining the mechanisms of specific toxicities and also in designing new drugs or new therapeutic protective protocols by specific competition at the transporter. Defining the pharmacogenomics of these transporters will be essential to personalized medicine, enabling physicians to choose drugs for patients based on efficacy, availability, cost, safety, tolerability and convenience.