高原缺氧对药物转运体影响的研究进展

高原具有的低氧、低气压等环境特点,会使机体产生一系列生理性变化,并影响药物的体内代谢过程。影响这个过程的因素有很多,包括胃排空、血液流变学、心肺功能、肝肾功能、药物代谢酶和药物转运体。其中,药物转运体是介导大部分药物透过细胞膜进入体内发挥药效的关键因素,研究缺氧对药物转运体的影响,对于明确药物的体内代谢过程具有重要的意义。因此,该文将从药物转运体的分类、介导的药物底物、缺氧对药物转运体表达的影响及缺氧条件下药物转运体的调控机制等方面进行综述,为深入研究高原缺氧对药物转运体的影响和药物代谢动力学参数变化提供理论依据。     

肠道菌群介导高原低氧对药物代谢的调节

高原低氧显著影响药物代谢动力学特征及药物代谢酶和转运体的活性和表达。肠道菌群是影响药物体内代谢的重要因素,可通过直接或间接作用影响药物代谢,改变药物的生物利用度、生物活性或毒性,进一步影响药物的疗效和安全性。高原低氧环境中肠道菌群的结构和多样性发生显著改变,在高原低氧条件下药物代谢的调节中可能发挥关键作用。本文旨在综述高原低氧对肠道菌群的影响及肠道菌群对药物代谢的影响,探讨肠道菌群介导的高原低氧对药物代谢的调节作用及相关机制。     

转运体介导的食物-药物相互作用

食物与药物之间的相互作用普遍存在,且作用机制也多种多样。目前,研究较多的是单个食物或食物中的某些营养成分通过调节药物转运体或代谢酶的功能从而影响药物的体内过程。食物对药物体内过程的影响包括吸收、分布、代谢、排泄四个方面,并且主要是调节其中参与的药物转运体和代谢酶的功能。转运体介导的食物对药物体内吸收的影响主要是通过调节肠上皮摄取型和外排型的转运体,从而影响药物的吸收;对分布的影响主要是通过调节体内一些屏障中的转运体;对代谢的影响主要是同时调节药物代谢酶和转运体;对排泄的影响是通过调节肾脏和肝脏胆汁排泄的药物转运体,从而影响药物的清除率。因此,转运体介导的食物与药物相互作用直接影响药物治疗的效果。     

孕烷X受体介导的代谢酶和转运体转录调控及其在化疗药物耐药中的作用

孕烷X受体(PXR,NR1I2)是生物体内药物代谢酶和转运体基因表达的主要调控因子之一.近来研究发现,PXR介导的药物代谢酶和转运体的过表达,与化疗药物多药耐药的产生密切相关.鉴于PXR在药物代谢酶和转运体调控中的重要性和PXR转录调控的多样性,有必要对其导致的多药耐药形成机制进行更深入的研究.本文综述了PXR介导的代谢酶和转运体基因表达调控机制,及其引起化疗药物多药耐药的相关研究进展,为提高化疗药物敏感性、逆转化疗药物的多药耐药提供有效的治疗策略.     

疾病状态下的药物代谢处置变化及其机制研究

疾病状态下药物代谢酶和药物转运体的异常调控会引起药物动力学过程的改变,进而影响药物疗效,甚至增加不良反应发生的风险。代谢酶/转运体异常调控的机制主要涉及炎症相关的信号通路/核受体、表观遗传修饰和蛋白质翻译后修饰等。系统回顾并总结了几类主要常见疾病状态下的药物代谢酶/转运体的调控变化及相关机制,同时介绍了生理药动学模型在指导疾病患者临床合理用药方面的应用,以期为基于疾病状态下药物代谢酶/转运体的安全有效的个体化用药提供借鉴和思路。     

microRNA对药物体内过程调控的研究进展

药物的体内过程需经一系列的生物转化和转运途径,依赖于药物代谢酶和转运体的参与。而个体对同一药物的代谢、转运能力存在差异,这一差异不能完全用药物基因组学解释。microRNA作为表观遗传修饰的一个重要方面,是对传统遗传学的强有力补充。人体内多种药物代谢酶和转运体均受到不同的microRNA调控,同一microRNA又可同时调控不同的代谢酶或(和)转运体,二者均提示microRNA极有可能实现较为广泛的宏观调控。该文分别从microRNA对药物代谢酶的调控、对药物转运体的调控以及同时调控代谢酶及转运体的microRNA三个方向综合分析,为研究药物个体差异提出一个极好的切入点,并为合理用药和个体化医疗提供理论基础。     

炎症反应过程中药物转运体调控的研究进展

炎症状态下机体对药物的处置过程会发生显著改变,众多药物代谢酶及转运体的表达和功能发生下调。研究表明机体在该状态下会释放一系列炎症细胞因子对药物代谢酶的表达和功能产生调控,而近年来的研究表明在炎症状态下药物转运体也受到这些细胞因子的调控,且部分转运体的调控呈现明显的种属差异性。进一步的机制研究表明,一些转录因子在调控的信号通路中发挥了重要的作用。本文对炎症状态下药物转运体的调控研究进展进行综述。     

转运体和核受体影响药物代谢的研究进展

转运体是存在于体内几乎所有器官上的有转运功能的蛋白,对药物在体内的吸收、分布、代谢和排泄有非常重要的作用.而核受体是存在于细胞内的配体依赖性转录因子,可以激活配体影响代谢酶和转运体的表达和活性,进而影响药物在机体内代谢.本文综述了转运体和核受体家族中几个重要的成员以及它们对药物代谢影响的研究进展.     

微小RNA对核受体调控药物代谢酶和转运体的研究现状

核受体(NRs)是一类配体依赖性转录因子超家族,通过内源性或外源性配体物质激活调控靶基因的转录。核受体在药物代谢酶和转运体的转录调控中发挥着重要的作用。微小RNA(MicroRNA)是一类内源性的具有调控功能的非编码RNA,其对核受体表达的改变可影响药物代谢酶和转运体的表达,进而影响药效、药物不良反应和药物相互作用。本文系统地综述microRNA对几种重要核受体调控药物代谢酶和转运体的影响。     

转运体和代谢酶在胆汁淤积性肝损伤中的作用机制

胆汁淤积性肝损伤是临床常见的肝脏疾病,主要由体内胆汁酸平衡失调引起,其发病机制与胆汁酸转运体、合成酶和代谢酶的表达和功能变化直接相关。核受体通过调控胆汁酸转运体及代谢酶的表达,在胆汁淤积所致的肝损伤中发挥重要作用。对肝脏转运体和代谢酶在胆汁淤积性肝损伤中的作用及核受体对转运体和代谢酶的调控机制作一综述。     

Genetically humanized mouse models of drug metabolizing enzymes and transporters and their applications

Abstract

1. Drug metabolizing enzymes and transporters play important roles in the absorption, metabolism, tissue distribution and excretion of various compounds and their metabolites and thus can significantly affect their efficacy and safety. Furthermore, they can be involved in drug–drug interactions which can result in adverse responses, life-threatening toxicity or impaired efficacy. Significant species differences in the interaction of compounds with drug metabolizing enzymes and transporters have been described.

2. In order to overcome the limitation of animal models in accurately predicting human responses, a large variety of mouse models humanized for drug metabolizing enzymes and to a lesser extent drug transporters have been created.

3. This review summarizes the literature describing these mouse models and their key applications in studying the role of drug metabolizing enzymes and transporters in drug bioavailability, tissue distribution, clearance and drug–drug interactions as well as in human metabolite testing and risk assessment.

4. Though such humanized mouse models have certain limitations, there is great potential for their use in basic research and for testing and development of new medicines. These limitations and future potentials will be discussed.     

The Role of Transporters in the Pharmacokinetics of Orally Administered Drugs

Drug transporters are recognized as key players in the processes of drug absorption, distribution, metabolism, and elimination. The localization of uptake and efflux transporters in organs responsible for drug biotransformation and excretion gives transporter proteins a unique gatekeeper function in controlling drug access to metabolizing enzymes and excretory pathways. This review seeks to discuss the influence intestinal and hepatic drug transporters have on pharmacokinetic parameters, including bioavailability, exposure, clearance, volume of distribution, and half-life, for orally dosed drugs. This review also describes in detail the Biopharmaceutics Drug Disposition Classification System (BDDCS) and explains how many of the effects drug transporters exert on oral drug pharmacokinetic parameters can be predicted by this classification scheme.     

代谢酶和转运体介导的草药-化学药相互作用安全性研究进展

目的 分析药物代谢酶和转运体介导的草药-化学药相互作用(herb-drug interactions,HDIs)和不良反应发生机制,总结常用草药与化学药物之间潜在相互作用的信息.方法 通过PubMed、Web of Science和中国知网等文献检索数据库,对草药、转运体、代谢酶等关键词进行文献检索.结果 草药与化学药...     

Herb-drug interactions involving drug metabolizing enzymes and transporters

Herbal medicines and their active ingredients are widely used worldwide, and they have become an important part of clinical medicine. The combined use of herbs and drugs has increased the possibility of pharmacokinetic and pharmacodynamic interactions. Clinical studies have demonstrated that the combined use of herbs and drugs can enhance or attenuate the drug efficacy and toxicity. The herb-drug combinations may reduce a drug efficacy and lead to treatment failure when long-term administration. Case reports detailing serious clinical adverse reactions have promoted studies on the interactions between herbs and drugs. This review highlights recent knowledge to discuss herb-drug interactions involving metabolizing enzymes and drug transporters. Drug transporters are widely present in body and play an important role in the absorption, distribution, excretion and metabolism, efficacy, and toxicity of drugs. Investigation of transporters has developed rapidly since 1990s, the effects of many transporters on the pharmacokinetics of drugs and herb-drug interactions have been reported. Some concepts on drug transporters issued experimentally and clinically drug-drug and herb-drug interactions have applied in many studies. Methodology studies are very important for understanding the mechanism, considerations and evaluation of experiments and clinical studies on drug metabolizing enzymes and transporters in drug-drug interactions.     

中西药相互作用的药代动力学机制研究进展

近年来,中西药联合应用日益增多,引起诸多药物相互作用和不良反应。药物代谢酶和转运体在药物的体内代谢和处置过程中发挥重要的作用,中西药联用不仅会改变药物的理化性质和人体的生理特性,而且可以调节药物代谢酶和转运体的表达和功能,进而产生药动学相互作用,引起药物疗效的改变。本文对中西药相互作用的药动学基础及其评价方法进行总结,旨在为中西药的联合应用和研究提供参考。     

大黄酸对药物转运体和代谢酶影响的研究进展

药物转运体和药物代谢酶是影响药物体内处置过程中至关重要的因素。大黄酸作为传统中药大黄的主要活性成分,具有广泛药理活性。研究发现,大黄酸与药物转运体和代谢酶密切相关,能够直接激活或抑制多种转运体的功能及其蛋白表达。而且大黄酸对药物代谢酶细胞色素P450（CYP450）的功能及其蛋白表达同样有抑制作用。因此,大黄酸与其他药物合用时,可能发生基于药动学的药物相互作用（drug-drug interaction,DDI）。从药物转运体和代谢酶的体内分布、大黄酸对转运体及代谢酶的影响等方面进行综述。     

CYP450s体外重组技术及在药物代谢和安全性评价中的应用

药物代谢是在代谢酶催化下完成的 ,它决定着药物的药理学和毒理学特性。根据动物实验来预测人体的药物代谢时 ,代谢酶的种属差异性会使这项研究工作变得非常困难。本文对含有人体代谢酶系的重组技术模型的应用进行了介绍和评价。从而有助于预测新药在人体中的代谢机制     

Why is it Challenging to Predict Intestinal Drug Absorption and Oral Bioavailability in Human Using Rat Model

Purpose To study the correlation of intestinal absorption for drugs with various absorption routes between human and rat, and to explore the underlying molecular mechanisms for the similarity in drug intestinal absorption and the differences in oral bioavailability between human and rat.Materials and Methods The intestinal permeabilities of 14 drugs and three drug-like compounds with different absorption mechanisms in rat and human jejunum were determined by in situ intestinal perfusion. A total of 48 drugs were selected for oral bioavailability comparison. Expression profiles of transporters and metabolizing enzymes in both rat and human intestines (duodenum and colon) were measured using GeneChip analysis.Results No correlation (r ² = 0.29) was found in oral drug bioavailability between rat and human, while a correlation (r ² = 0.8) was observed for drug intestinal permeability with both carrier-mediated absorption and passive diffusion mechanisms between human and rat small intestine. Moderate correlation (with r ² > 0.56) was also found for the expression levels of transporters in the duodenum of human and rat, which provides the molecular mechanisms for the similarity and correlation of drug absorption between two species. In contrast, no correlation was found for the expressions of metabolizing enzymes between rat and human intestine, which indicates the difference in drug metabolism and oral bioavailability in two species. Detailed analysis indicates that many transporters (such as PepT1, SGLT-1, GLUT5, MRP2, NT2, and high affinity glutamate transporter) share similar expression levels in both human and rat with regional dependent expression patterns, which have high expression in the small intestine and low expression in the colon. However, discrepancy was also observed for several other transporters (such as MDR1, MRP3, GLUT1, and GLUT3) in both the duodenum and colon of human and rat. In addition, the expressions of metabolizing enzymes (CYP3A4/CYP3A9 and UDPG) showed 12 to 193-fold difference between human and rat intestine with distinct regional dependent expression patterns.Conclusions The data indicate that rat and human show similar drug intestinal absorption profiles and similar transporter expression patterns in the small intestine, while the two species exhibit distinct expression levels and patterns for metabolizing enzymes in the intestine. Therefore, a rat model can be used to predict oral drug absorption in the small intestine of human, but not to predict drug metabolism or oral bioavailability in human.