浅谈中药成分体内代谢研究

传统中药多为口服用药,这决定了中药成分在体内发挥药效的形式具有多样性。中药在体内发挥药效的物质可能是中药中的化学成分,还可能是中药成分在体内的代谢产物。尽管中药化学成分研究在过去的30年里取得了令人瞩目的成就,但中药成分的体内代谢研究一直进展缓慢。本文针对目前研究现状提出加快该领域研究的一些建议和想法,并通过一些研究实例揭示中药成分体内代谢研究在阐明中药药效物质等方面的作用。     

体外模型在中药代谢研究中的应用

体内代谢研究对阐明中药药效物质基础及作用机制有重要意义。体外模型由于其替代、简化和精准的特点,已成为中药体内代谢研究的重要手段之一。综述药物体内过程研究中常用的体外模型及其特点,并总结其在中药代谢研究中的应用概况,以期为中药成分代谢研究提供理论和方法学参考。     

皂苷类成分吸收分布和代谢及排泄研究进展

皂苷是一类具有多种药理活性的重要天然产物,但由于其生物利用度普遍较低,体内的药效物质基础和作用机制研究尚不够深入,影响了该类成分的新药开发与应用。本文对近年来国内外关于皂苷类化合物体内外代谢等过程研究的文献进行综述,有利于深入探索该类成分的体内药效物质基础和作用机制,为新药研发提供一定的理论依据。     

基于代谢组学的中药代谢动力学研究思路探讨

代谢组学高通量、整体性的研究技术和研究思路,对中药中活性物质的分析方法及其代谢产物的药代动力学分析提供了新思路,有助于揭示中医证候的科学内涵和开展中药现代化研究。生命体．疾病．中药作用是一个动态的、紧密联系的整体过程,代谢组学则是连接的枢纽和中心,其全景式、整体互动性的特点与中医药的整体观念、证候的复杂体系及动态连贯性、中药作用的多靶点和突出整体效应不谋而合,是中医药现代化的最佳切入点。中药进入生命体后,起效的是中药中的原形成分或代谢产物,或与机体作用形成的新成分,三者构成体内中药成分的代谢物组。而中药代谢物组通过多靶点、多系统,协调干预人体内源性代谢物组来治疗疾病,所产生的一系列变化实质上仍然是代谢动力学变化,如能科学阐明原方成分与体内代谢成分的规律,自然能揭示中药成分的代谢规律,因此推动与基因组学——蛋白质组学相关联的代谢组学和成分组学的研究,从根本上解决中药的药动学问题。     

一测多评中药质量控制研究进展

一测多评(QAMS)是近年来新兴的中药质量控制方法,能够在缺少对照品的情况下实现多成分质量控制。迄今,QAMS报道的中药材、饮片以及中药制剂已达数十种。植物次级代谢产物是多数中药发挥药效作用的物质基础,也是评价相应中药质量优劣的关键。本文从植物次级代谢产物的角度,综述了近年来QAMS在中药质量评价中的研究进展,为该方法进一步的研究和应用提供了参考。     

驱虫斑鸠菊血清药物化学的初步研究

［摘要］目的对维药驱虫斑鸠菊进行血清药物化学研究,探讨驱虫斑鸠菊药效作用的物质基础。方法在建立驱虫斑鸠菊高效液相色谱（HPLC）指纹图谱的基础上,通过比较驱虫斑鸠菊水提取物、驱虫斑鸠菊含药血清和空白血清HPLC指纹图谱的差异,确定驱虫斑鸠菊血中移行成分。结果在驱虫斑鸠菊含药血清中发现了9种入血成分,其中5种为原型成分,其余4种可能为原型成分的代谢产物。结论9种入血成分可能是驱虫斑鸠菊的体内直接作用物质,对其进行深入研究将有助于阐明驱虫斑鸠菊的药效物质基础及药效机制。     

基于UPLC-Q/TOF-MS的甘草酸单铵和甘草酸二铵在大鼠体内移行成分表征

目的 采用超高效液相色谱-四极杆/飞行时间高分辨质谱技术(UPLC-Q/TOF-MS)对甘草酸单铵和甘草酸二铵在大鼠体内的代谢轮廓进行表征，探讨两者可能的代谢途径。方法 大鼠分别灌胃给予甘草酸单铵和甘草酸二铵后，收集不同时间点大鼠脑组织、血浆、尿液、粪样等生物样本。经沉淀蛋白后，采用UPLC-Q/TOF-MS技术，以含0.1%甲酸的水-乙腈为流动相进行梯度洗脱；在正离子模式下采集生物样本的质谱数据。采用质量残差亏损过滤技术并结合原型成分的质谱裂解规律，预测代谢物类型，对两者相关的体内代谢产物进行鉴定。结果 甘草酸单铵和甘草酸二铵在大鼠体内主要以代谢物形式存在，共鉴定得到20个代谢产物，两者主要通过肠道排泄，在体内原型化合物脱糖基形成的甘草次酸基础上发生一系列的Ⅰ相氧化还原反应是主要代谢类型；甘草次酸是在生物样本中主要暴露成分，提示了其可能是甘草酸单铵及甘草酸二铵在体内发挥药效的关键药效成分。结论 首次阐明了甘草酸单铵及甘草酸二铵在大鼠体内的代谢轮廓，为进一步对两者发挥功效作用的物质基础及药效作用机制揭示和开发利用提供参考。     

中药多组分体内过程与药效关联研究的探索

目前,威胁人类健康的主要疾病从传染性疾病向慢性非传染性疾病如肿瘤、心脑血管疾病等转变,该类疾病的发生发展是由多因素所导致的。而中药有效组分能够通过对机体多途径、多靶点的调节作用,进而达到标本兼治、综合调理的目的,对这类慢性非传染性疾病有着独特的治疗作用。然而,由于中药具有多成分多靶点、代谢复杂、药效输出广泛的特点,是中药研究中的重大科学问题之一。本团队创建了中药多组分药代动力学研究过程中的诸多关键技术,包括"特征诊断离子延伸"策略,"质量亏损过滤"策略和"诊断离子桥联网络"策略等,这些关键技术的实施基本解决了中药体内外物质组测定难的问题,得到了国内外同行的高度认可。在解决了中药多组分测定的基础上,围绕中药药动学研究的实际问题,通过药动学、药效学、代谢组学、化学信息学等多学科结合手段,自主创新,构建了中药体内外物质组关联分析技术、中药同系成分定量构代(QSMR)研究技术和中药药动学参数拓展分析技术三大中药药动学关键技术,形成了中药药动学研究的技术新体系,促进了中药药动学的研究。与此同时,由于中药成分群在生物体内代谢的广泛性,给中药体内药效物质基础解析带了极大挑战,传统的沿用化学药物经典代谢理论和技术并不适用于中药多组分代谢的研究,亟待突破。因此,本团队提出了中药"多向代谢"新理论,指出中药代谢途径包括:(1)Ⅰ/Ⅱ相代谢:经由经典的Ⅰ相和Ⅱ相代谢反应,产生新的物质;(2)量变代谢:中药同系成分群发生水解、降解等代谢反应,不产生新的物质,但改变了原中药同系成分群各成分的构成比;(3)内化代谢:经多步生物转化最终代谢成为人体内源性代谢中间体,整合到人体代谢过程中发挥药效作用。中药的这3类代谢反应,均可能通过不同的方式对其整体药效作用产生显著影响,包括产生新的活性代谢产物、改变有效成分构成比和整合调控生物体内源代谢网络等3种方式。阐明中药这3类代谢与整体药效作用的关系,是突破中药体内药效物质基础研究的核心科学问题。将上述新理论和新技术体系应用于名优中药及经典方剂等研究,对中药组分与药效关联研究以及中西药临床联合用药的机制研究进行了广泛而深入的探索,在解释中医中药的科学性、推进中药国际化和现代化中具有重要意义。     

哈巴苷在大鼠体内代谢产物的鉴定与分析

目的:研究玄参活性成分哈巴苷在大鼠体内的代谢产物及其分布、代谢类型和其可能的活性。方法:4只SD大鼠随机分为空白组(超纯水)和给药组(哈巴苷对照品溶液),每组2只,ig给药,160 mg/kg,每日2次,连用3 d。于给药前及首次给药后每12h收集各组大鼠尿液和粪便,最后1次给药后0.5、1 h穿心取血8 mL并取出心、肝、脾、肺、肾、胃和小肠等组织,分别制备血液、尿液、粪便及各组织样品溶液。采用高效液相色谱-质谱联用法检测和鉴定哈巴苷在大鼠体内的代谢产物并推测其代谢途径,采用PharmMapper软件预测代谢产物活性。结果:从大鼠体内鉴定出哈巴苷代谢产物12种,其原型及代谢产物主要分布在心、肝、脾、肺、肾、胃和小肠中,其代谢类型主要包括水解、脱水、还原、甲基化、硫酸酯化、葡萄糖醛酸结合、一级香豆酸结合等。12种化合物可能具有治疗癫痫、肌萎缩侧索硬化、糖尿病、脑中风等活性。结论:哈巴苷可能是以原型和代谢产物的形式发挥药效的。本研究为归属玄参体内代谢产物来源、研究玄参显效形式、阐明玄参药理作用机制和炮制机制提供了依据。     

肝体外代谢在中药活性成分研究中的应用进展

药物代谢系指药物进入体内后,在机体作用下发生的化学结构转化,即生物转化(Drug Biotransformation).转化在体内酶的作用下进行,能把外源性的物质进行化学处理,从而引起药物的药理活性和毒理活性的改变.近年来,模拟体内代谢过程的体外代谢研究方法迅速发展,通过离体器官、细胞或酶系统进行体外代谢研究[1].中药是一个复杂的体系,其有效成分或单体也作用于药物代谢酶系统,中药的体外代谢研究可以在短时间内得到大量的代谢产物,推断药物可能的代谢途径及参与代谢的酶,计算体内药物代谢的清除率,研究药物的相互作用[2],更好解释中药有效成分的作用机理,同时增强临床用药安全,为新药研究提供基础.     

Chemical metabolism of medicinal compounds from natural botanicals

Traditional Chinese medicine (TCM) and its natural products are complex mixtures containing hundreds of chemically different constituents but only a few components are responsible for the pharmacological effects and bioactivities. In order to clarify the functional mechanism of active compounds, the studies on metabolism are of great significance and necessity. Previously, research mainly focused on the aspect of pharmacokinetics, however in recent years, chemical metabolism of active compounds has drawn increasing attention. Researches on the chemical metabolism of single phytochemicals help to understand the transformation process in vivo and mechanism of action, also contribute to pharmacodynamics and toxicology studies and new drug development. In the present paper, the chemical metabolism of nine categories of phytochemicals was reviewed. This review focused on pharmacological action, metabolic characteristics, metabolic pathways, metabolites and assay method of alkaloids, flavonoids, saponins, terpenoids, stilbenes, phenols, quinones, lignans and esters. The parent drugs, perhaps the metabolites, or they together play a role in pharmacological effects. And different routes of administration may lead to different results of transformation pathways and metabolites. Moreover, high-tech assay methods, particularly the combined use of modern instrument analytical techniques, are beneficial to the research of drug metabolism.     

液相色谱-质谱联用技术在中药方剂现代研究中的应用进展

液相色谱与质谱联用技术(LC-MS)将液相色谱的高分离效能与质谱的结构鉴定功能结合起来,已逐渐成为方剂现代研究的强有力手段.本文从液相色谱与质谱联用技术在各类型化合物裂解规律研究、方剂中效应成分快速定性定量分析、方剂配伍规律研究、方剂效应物质的体内代谢研究等方面的应用进展进行了综述,并对该技术目前在方剂研究中存在的问题及应用前景进行展望.     

Constituents in kava extracts potentially involved in hepatotoxicity: a review

Aqueous kava root preparations have been consumed in the South Pacific as an apparently safe ceremonial and cultural drink for centuries. However, several reports of hepatotoxicity have been linked to the consumption of kava extracts in Western countries, where mainly ethanolic or acetonic extracts are used. The mechanism of toxicity has not been established, although several theories have been put forward. The composition of the major constituents, the kava lactones, varies according to preparation method and species of kava plant, and thus, the toxicity of the individual lactones has been tested in order to establish whether a single lactone or a certain composition of lactones may be responsible for the increased prevalence of kava-induced hepatotoxicity in Western countries. However, no such conclusion has been made on the basis of current data. Inhibition or induction of the major metabolizing enzymes, which might result in drug interactions, has also gained attention, but ambiguous results have been reported. On the basis of the chemical structures of kava constituents, the formation of reactive metabolites has also been suggested as an explanation of toxicity. Furthermore, skin rash is a side effect in kava consumers, which may be indicative of the formation of reactive metabolites and covalent binding to skin proteins leading to immune-mediated responses. Reactive metabolites of kava lactones have been identified in vitro as glutathione (GSH) conjugates and in vivo as mercapturates excreted in urine. Addition of GSH to kava extracts has been shown to reduce cytotoxicity in vitro, which suggests the presence of inherently reactive constituents. Only a few studies have investigated the toxicity of the minor constituents present in kava extract, such as pipermethystine and the flavokavains, where some have been shown to display higher in vitro cytotoxicity than the lactones. To date, there remains no indisputable reason for the increased prevalence of kava-induced hepatotoxicity in Western countries.     

Nicotine metabolism in mammals

Over the past decade studies on nicotine metabolism have been advanced by use of new methods involving enzyme purification, preparation of specific antibodies and HPLC. In in vivo experiments of nicotine metabolism, a number of new metabolites have been identified, and most major and minor metabolites have been quantitatively determined, which make it now possible to investigate the contribution of each pathway to overall nicotine metabolism. In in vitro experiments, C-oxidation and N-oxidation have been precisely characterized. Despite extensive investigations, metabolic regulation of nicotine metabolism still remains unclear.     

亚麻子化学成分及其药理作用研究进展

亚麻子含有大量的木脂素类化合物,以原形化合物或在人体内被代谢后产生较强的生物活性物质而发挥抗肿瘤和降血糖作用等,现已被开发成保健药品.该中药的化学成分除含有主要的木脂素类化合物外,尚含有黄酮类、环肽类、生氰葡糖苷类、苯丙素葡糖苷类等化合物.现对近几十年来国内外有关亚麻子的化学成分、药理作用及代谢等方面研究成果进行综述,为全面开发利用亚麻子提供科学依据.     

Strategies for integral metabolism profile of multiple compounds in herbal medicines: pharmacokinetics, metabolites characterization and metabolic interactions

Herbal medicines (HMs) are gaining more and more attention all over the world, because of their significant curative effect in treating multi-factorial diseases. Recently, the in vivo and in vitro metabolism study of HMs has become an important issue because these data can help us to better understand the efficacies and toxicities of HMs. However, the integral metabolism profile of HMs is confronted with many challenges: 1) HM is a multi-component system; 2) most components are unknown (nontarget); 3) trace of components in HM. Given the challenges described above, the demand for more powerful bioanalytical tools and strategies that are adequate for integral metabolism profile of HMs' multi-components has increased. In the past few years, newer methods, or adaptations to methods, have been published, and this review will attempt to discuss new improvements in strategies and methodologies for HMs' multi-component ADME evaluation. In particular, improvements have been reported for experimental approaches to pharmacokinetics study of HMs, as well as strategies applied to metabolites characterization of HMs' multi-components, and the metabolic interactions between ingredients in HMs, including advance and proposed strategy: "chemical fishing" based strategy for metabolic interactions of HMs.     

METABOLIC ACTIVATION AS A BASIS FOR ORGAN-SELECTIVE TOXICITY

Historically, the concept of metabolic activation was first forwarded to explain the in vivo activity of certain carcinogenic chemicals that without prior metabolism were chemically inert and biologically inactive. Subsequently, the concept has been extended to explain the effects of many different classes of chemicals causing diverse toxicities. Because of its major role in drug metabolism, the liver is a prominent site for toxic injury by agents requiring metabolic activation. The liver can also be the source of reactive metabolites that damage extrahepatic organs. But, organ selective toxicity can also result from the in situ metabolic activation of foreign chemicals in extrahepatic target tissues such as the lungs and the kidneys. Moreover, extrahepatic tissues generally are much more heterogeneous in cellular composition compared to the liver, and the localization of drug metabolizing enzymes in certain cell populations may result in highly cell selective toxic injury. The significance of metabolic activation and toxicity--and the importance of the particular chemical structure of individual compounds, as well as host factors such as species, age, sex, and pretreatment effects--on target-organ-selective toxicity by reactive metabolites are illustrated by studies with various furan derivatives, an important class of environmental chemicals.     

人参皂苷体内代谢及其产物的生物活性

人参皂苷(ginsenoside)是从人参中提取出来的萜类化合物,是人参诸多药理药效作用的主要活性成分。天然人参皂苷口服难以被直接吸收,必须经过体内代谢后,其产物才能发挥生物活性。然而,迄今国内尚未检索到人参皂苷体内代谢过程比较系统的研究报道。因此,本文从以下4个方面概述下人参皂苷在体内的代谢研究:一是人参皂苷胃酸液、肠道菌、其他微生物的去糖基化;二是代谢产物通过被动扩散的方式进行吸收;三是代谢产物在肝脏中的酯化和聚集;四是代谢产物的生物活性。     

Are chemically reactive metabolites responsible for adverse reactions to drugs?

Low molecular weight organic chemicals can be transformed by normal drug-metabolising systems into short-lived metabolites that are inherently reactive towards cellular macromolecules. There is direct evidence that the formation of such chemically reactive metabolites may lead to mutagenesis, carcinogenicity, apoptosis and necrosis in both cell and animal models. A number of drugs associated with non-pharmacological drug toxicities in man have been shown to undergo bioactivation either in vivo or in vitro. We have therefore examined the evidence for the role of reactive metabolites in the three most common drug-induced toxicities: hepatotoxicity, skin reactions and blood dyscrasias.