临床药师要关注药物的代谢转化

药物进入体内后，经有关酶的催化，进行化学变化，称代谢转化。药物经转化后水溶性增高，有利于排泄体外。多数情况代谢产物的活性或毒性降低，但也有不少实例经代谢转化后代谢产物药理活性或毒性增高。药物的酶促代谢不只通过单一途径，产生的也不仅单一产物，每个代谢产物的药理活性或毒性不同，而每个病人的酶活性有所不同，对通过这些途径的速率相异，可表现为药物效应或毒性的个体差异。临床药师观察到病人所表现的不同反应往往可用代谢转化的观点解释，因而临床药师要关注药物的代谢转化，以便协助医师更适当、更安全有效地用药。     

化合物结构与代谢激活的毒性分析

药物开发的不同阶段，人们通过系列的体外试验研究、动物实验以及随后人体应用的结果试图揭示药物的毒副作用，目的是为确保人体用药的安全性。其中代谢转化诱导的毒性占据药物毒性的很大一方面，尤其反应性代谢产物引发的毒性近几年越来越引起重视。本文综述了几类代表性化合物结构产生反应性代谢产物的情况，包括苯醌亚胺、噻吩环、氮翁离子、环氧化物、硫脲等，试图从代谢角度揭示药物分子结构与药物毒性之间的关系，为药物的设计与开发提供参考。     

药物代谢转化及对其活性的影响

药物进入体内后，经有关酶的催化，发生化学变化，称代谢变化。药物转化后水溶性增高，有利于排出体外，多数药物的代谢产物活性或毒性降低，但也有不少药物经代谢转化后活性或毒性增强，在开发或使用药物时应引起注意。酶促代谢不只通过单一途径，每个人酶活力不一，可表现为药物效应的个体差异。适当修饰药物的化学结构，可阻滞加束 代谢转化，从而改变药效的长短。     

药物性肝炎的临床病因及相关治疗研究

肝脏是各种药物在体内代谢的场所,内源性或外源性亲脂性化学制剂经肝脏代谢过程中常产生各种具有反应性的中间产物,其能攻击大分子物质导致产生直接毒性或超敏反应性。多种药物均可引起各种肝病,从无症状的肝功能试验异常到爆发性肝炎。本文就药物性肝炎的临床发病机制及相关治疗做出综述。     

代谢活化引起的药物毒性及其防止的若干途径

药物代谢活化的一般概念药物和外源性化合物进入体内后,一般经两相代谢转化。第一相包括氧化、还原和水解;第二相主要为结合反应,包括葡萄糖醛酸甙化、硫酸酯化、酰化、甲基化及与氨基酸结合等。大多数药物经代谢后,活性降低,极性变大,水溶性增强,从而迅速排出体外,通常称之为生物解毒。部分药物则转化为更具有治疗作用的代谢物;但也有相当一部分药物经代谢后能形成高度反应性的中间体,即所谓代谢活化。不少药     

药物肝代谢研究方法进展

<正>药物代谢是指药物在体内经历的化学结构的变化过程, 也称为生物转化。药物在体内的代谢大多是酶系统催化反应。药物通过代谢起到解毒作用,但也常常会出现代谢产物毒性更强;有的药物本身没有活性,但进入体内后,代谢产物具有活性。因此药物代谢研究非常重要。     

液相色谱质谱联用检测药物反应性代谢物的研究进展

候选药物在体内向反应性代谢物的生物转化过程中,人们不希望其生成能共价结合大分子(如蛋白质和DNA)的反应性代谢物。作为候选药物吸收、分布、代谢和排泄(ADME)性质整体评价的一部分,许多制药公司已开始采用多种体内外筛选方法研究其是否有生成反应性代谢物的可能,并鉴定反应性代谢物的性质。发现问题化合物后,通过合适的结构修饰使潜在的生物转化减少至最低。因此,检测、鉴定和定量测定活性代谢产物在药物开发过程中非常重要。三级四极杆质谱是用于分析活性代谢产物的常规方法。在过去3年间,为改善分析灵敏度和选择性,实现高通量筛选,已发展了许多新的质谱方法。本文重点阐述在药物开发过程中应用液相色谱质谱联用(LC-MS/MS)检测和鉴定反应性代谢物的最新进展,尤其关注线性离子阱(LTQ)、混合三级四极杆-线性离子阱(Q-trap)和高分辨LTQ-静电场轨道阱的应用。     

深度学习模型在中药毒性预警中的应用和前景

中药潜在毒性成分的早期筛查是中药新药研发面临的一大难题.在基于"结构预警子-毒性"关系开发的机器学习模型中,使用深度学习算法构建的机器学习模型脱颖而出,有望成为新一代中药毒性预测的杰出工具.本文综述了深度学习模型基于"结构预警子-毒性"关系预测化合物毒性的机制以及深度学习模型在预测药物分子的毒性、预测反应性代谢产物的形...     

新药研发过程中毒理学研究方法的进展--毒性的原因和早期毒性筛选

毒性已成为新药开发过程中淘汰的主要原因。近年来制药和生物技术工业的研究人员开发了多种新技术以便在药物发现和开发过程中尽早确定化合物的安全特性。笔者首先对药物毒性产生的原因如药靶的特异性、药物的分子结构、药物代谢和代谢动力学等方面进行了分析，再介绍了近几年早期毒性筛选的新技术，包括预测模型、体外高通量毒性筛选、活性代谢产物的检测、高内涵筛选技术、动物实验。     

肠道细菌对天然药物代谢的研究进展Ⅰ

目的:介绍肠道细菌对天然药物代谢的最新研究进展。方法:综述近年来国内外相关文献,对黄酮、皂苷、木脂素、环烯醚萜苷类等天然产物在肠道细菌作用下的代谢情况进行总结归纳。结果:天然产物经肠道细菌代谢后,转化为具有药理或毒理活性的新化合物。结论:许多天然药物以前药形式存在,肠道细菌在其代谢中发挥着至关重要的作用     

The role of leukocyte-generated reactive metabolites in the pathogenesis of idiosyncratic drug reactions.

Evidence strongly suggests that many adverse drug reactions, including idiosyncratic drug reactions, involve reactive metabolites. Furthermore, certain functional groups, which are readily oxidized to reactive metabolites, are associated with a high incidence of adverse reactions. Most drugs can probably form reactive metabolites, but a simple comparison of covalent binding in vitro is unlikely to provide an accurate indication of the relative risk of a drug causing an idiosyncratic reaction because it does not provide an indication of how efficiently the metabolite is detoxified in vivo. In addition, the incidence and nature of adverse reactions associated with a given drug is probably determined in large measure by the location of reactive metabolite formation, as well as the chemical reactivity of the reactive metabolite. Such factors will determine which macromolecules the metabolites will bind to, and it is known that covalent binding to some proteins, such as those in the leukocyte membrane, is much more likely to lead to an immune-mediated reaction or other type of toxicity. Some reactive metabolites, such as acyl glucuronides, circulate freely and could lead to adverse reactions in almost any organ; however, most reactive metabolites have a short biological half-life, and although small amounts may escape the organ where they are formed, these metabolites are unlikely to reach sufficient concentrations to cause toxicity in other organs. Many idiosyncratic drug reactions involve leukocytes, especially agranulocytosis and drug-induced lupus. We and others have demonstrated that drugs can be metabolized by activated neutrophils and monocytes to reactive metabolites. The major reaction appears to be reaction with leukocyte-generated hypochlorous acid. Hypochlorous acid is quite reactive, and therefore it is likely that many other drugs will be found that are metabolized by activated leukocytes. Some neutrophil precursors contain myeloperoxidase and the NADPH oxidase system, and it is likely that these cells can also oxidize drugs. Therefore, although there is no direct evidence, it is reasonable to speculate that reactive metabolites generated by activated leukocytes, or neutrophil precursors in the bone marrow, could be responsible for drug-induced agranulocytosis and aplastic anemia. This could involve direct toxicity or an immune-mediated reaction. These mechanisms are not mutually exclusive, and it may be that both mechanisms contribute to the toxicity, even in the same patient. In the case of drug-induced lupus, a prevalent hypothesis for lupus involves modification of class II MHC antigens.(ABSTRACT TRUNCATED AT 400 WORDS)     

Mechanism of idiosyncratic drug reactions: reactive metabolite formation,protein binding and the regulation of the immune system

Drug-induced adverse reactions, especially type B reactions, represent a major clinical problem. They also impart a significant degree of uncertainty into drug development because they are often not detected until the drug has been released onto the market. Type B reactions are also termed idiosyncratic drug reactions by many investigators due to their unpredictable nature and our lack of understanding of the mechanisms involved. It is currently believed that the majority of these reactions are immune-mediated and are caused by immunogenic conjugates formed from the reaction of a reactive metabolite of a drug with cellular proteins. It has been shown that most drugs associated with idiosyncratic reactions form reactive metabolites to some degree. Covalent binding of reactive metabolites to cellular proteins has also been shown in many cases. However, studies to reveal the role of reactive metabolites and their protein-adducts in the mechanism of drug-induced idiosyncratic reactions are lacking. This review will focus on our current understanding and speculative views on how a reactive metabolite of a drug might ultimately lead to immune-mediated toxicity.     

Managing the challenge of chemically reactive metabolites in drug development

The normal metabolism of drugs can generate metabolites that have intrinsic chemical reactivity towards cellular molecules, and therefore have the potential to alter biological function and initiate serious adverse drug reactions. Here, we present an assessment of the current approaches used for the evaluation of chemically reactive metabolites. We also describe how these approaches are being used within the pharmaceutical industry to assess and minimize the potential of drug candidates to cause toxicity. At early stages of drug discovery, iteration between medicinal chemistry and drug metabolism can eliminate perceived reactive metabolite-mediated chemical liabilities without compromising pharmacological activity or the need for extensive safety evaluation beyond standard practices. In the future, reactive metabolite evaluation may also be useful during clinical development for improving clinical risk assessment and risk management. Currently, there remains a huge gap in our understanding of the basic mechanisms that underlie chemical stress-mediated adverse reactions in humans. This review summarizes our views on this complex topic, and includes insights into practices considered by the pharmaceutical industry.     

Evaluation of felbamate and other antiepileptic drug toxicity potential based on hepatic protein covalent binding and gene expression

Felbamate is an antiepileptic drug that is associated with minimal toxicity in preclinical species such as rat and dog but has an unacceptable incidence of serious idiosyncratic reactions in man. Idiosyncratic reactions account for over half of toxicity-related drug failures in the marketplace, and improving the preclinical detection of idiosyncratic toxicities is thus of paramount importance to the pharmaceutical industry. The formation of reactive metabolites is common among most drugs associated with idiosyncratic drug reactions and may cause deleterious effects through covalent binding and/or oxidative stress. In the present study, felbamate was compared to several other antiepileptic drugs (valproic acid, carbamazepine, phenobarbital, and phenytoin), using covalent binding of radiolabeled drugs and hepatic gene expression responses to evaluate oxidative stress/reactive metabolite potential. Despite causing only very mild effects on covalent binding parameters, felbamate produced robust effects on a previously established oxidative stress/reactive metabolite gene expression signature. The other antiepileptic drugs and acetaminophen are known hepatotoxicants at high doses in the rat, and all increased covalent binding to liver proteins in vivo and/or to liver microsomes from human and rat. With the exception of acetaminophen, valproic acid exhibited the highest covalent binding in vivo, whereas carbamazepine exhibited the highest levels in vitro. Pronounced effects on oxidative stress/reactive metabolite-responsive gene expression were observed after carbamazepine, phenobarbital, and phenytoin administration. Valproic acid had only minor effects on the oxidative stress/reactive metabolite indicator genes. The relative ease of detection of felbamate based on gene expression results in rat liver as having potential oxidative stressor/reactive metabolites indicates that this approach may be useful in screening for potential idiosyncratic toxicity. Together, measurements of gene expression along with covalent binding should improve the safety assessment of candidate drugs.     

2,7-Disubstituted-pyrrolotriazine kinase inhibitors with an unusually high degree of reactive metabolite formation

There are numerous published studies establishing a link between reactive metabolite formation and toxicity of various drugs. Although the correlation between idiosyncratic reactions and reactive metabolite formation is not 1:1, the association between the two is such that many pharmaceutical companies now monitor for reactive metabolites as a standard part of drug candidate testing and selection. The most common method involves in vitro human microsomal incubations in the presence of a thiol trapping agent, such as glutathione (GSH), followed by LC/MS analysis. In this study, we describe several 2,7-disubstituted-pyrrolotriazine analogues that are extremely potent reactive metabolite precursors. Utilizing a UPLC/UV/MS method, unprecedented levels of GSH adducts were measured that are 5-10 times higher than previously reported for high reactive metabolite-forming compounds such as clozapine and troglitazone.     

Conventional and novel approaches in generating and characterization of reactive intermediates from drugs/drug candidates

Despite several thousands of drugs are in use currently, research on new drug molecules is continuing. Because, there are diseases still without medication, successor/better drugs make the predecessor ones obsolete, and advancement in both life sciences and analytical technologies provide identification of previously unknown mechanisms of diseases, and discovery of novel drug targets. The two main criteria which a drug candidate should meet are high affinity for the target, and no or acceptable/tolerable toxicity in humans. Among these two, toxicity is the limiting one; developing a drug candidate with unacceptable toxicity has to be discontinued, even if it has an extremely high pharmacological activity. Drug would be withdrawn, if serious toxicity arises after marketing. Since drug development is a long (approximately 10 years), expensive, and infertile (one lead in 10.000 molecules) process, it is extremely important to detect the potential toxicity of drug candidate as early as possible. Today, it is believed that a great majority of toxic effects are caused by reactive intermediates generated by biotransformation of the parent drug. However, there are experimental difficulties in identifying such metabolite(s) in vivo. Their formation is affected by multi-factorial events; they can further be metabolized to structurally different products, and/or they may bind to a huge variety of biological sites or macromolecules. Hence, some reactive intermediates and their corresponding stable derivatives are generated in trace amounts, which make their determination more difficult. The ability of cytochrome P450s (CYP450) and other biotransformation enzymes to function in vitro offers a great flexibility to researchers, biotransformation of any compound can be simulated in a test tube, and metabolites/reactive intermediates are generated in an environment which has relatively much less background and less interfering multi-factorial events compared to in vivo. To simulate biotransformation, microsomal fraction is used most frequently from human and non-human sources. Purified or recombinant enzymes are used in determining the individual isoenzymes responsible for certain metabolites. Because of the chemical reactivity of intermediates, relevant, usually nucleophilic trapping agent(s) such as glutathione (GSH), N-acetylcysteine (NAC) and cyanide (CN-) are used to stabilize the metabolite. Trapped metabolites are subjected to spectrometric and/or nuclear magnetic resonance spectroscopic analyses for structural identification. Vertiginous advances especially in mass spectrometric technologies offer researchers new challenges in this area. This review is aimed at briefly summarizing the state of the art and compiling the highlighted studies in characterization of the reactive metabolites from drug molecules.     

Pharmacodynamics of TNF-α inhibitors in psoriasis

It is generally accepted that bioactivation of relatively inert functional groups (toxicophores) to reactive metabolites is an obligatory step in the pathogenesis of certain idiosyncratic adverse drug reactions (IADRs). IADRs cannot be detected in regulatory animal toxicity studies and, given their low frequency of occurrence in humans (1 in 10,000 to 1 in 100,000), they are often not detected until the drug has gained broad exposure in a large patient population. The detection of IADRs during late clinical trials or after a drug has been released can lead to an unanticipated restriction in its use, and even in its withdrawal. To date, there is neither a consistent nor a well-defined link between bioactivation and IADRs; however, the potential does exist for these processes to be causally related. Thus, the formation of reactive metabolites with a drug candidate is generally considered a liability in most pharmaceutical companies. Procedures have been implemented to evaluate bioactivation potential of new drug candidates with the goal of eliminating or minimizing reactive metabolite formation by rational structural modification of the lead chemical class. While such studies have proven extremely useful in the retrospective analysis of bioactivation pathways of toxic drugs and defining toxicophores, their ability to accurately predict the IADR potential of new drug candidates has been challenged, given that several commercially successful drugs form reactive metabolites, yet, they are not associated with a significant incidence of IADRs. In this article, we review the basic methodology that is currently utilized to evaluate the bioactivation potential of new compounds, with particular emphasis on the advantages and limitation of these assays. Plausible reasons for the excellent safety record of certain drugs susceptible to bioactivation are also explored. Overall, these observations provide valuable guidance in the proper use of bioactivation assessments when selecting drug candidates for development.     

Evaluation of which reactive metabolite, if any, is responsible for a specific idiosyncratic reaction

Reactive metabolites are believed to be responsible for most idiosyncratic drug reactions. It is often assumed that if a reactive metabolite is found, it must be responsible for the idiosyncratic reactions associated with that drug. However, the evidence linking reactive metabolites and idiosyncratic reactions is circumstantial at best, and in many cases we have virtually no evidence. Furthermore, it is common for a drug to form several reactive metabolites, so it can be difficult to determine which, if any, is responsible for a given idiosyncratic reaction. Although the reactive metabolite hypothesis is logical, it has important implications for drug development, and we need to develop ways to test the hypothesis for specific drugs rigorously. Valid animal models are a powerful tool for testing whether a specific reactive metabolite is responsible for a specific adverse reaction and for studying further the mechanism by which it may induce such reactions; however, such models are rare.     

Evaluation of Which Reactive Metabolite,If Any,Is Responsible for a Specific Idiosyncratic Reaction

Reactive metabolites are believed to be responsible for most idiosyncratic drug reactions. It is often assumed that if a reactive metabolite is found, it must be responsible for the idiosyncratic reactions associated with that drug. However, the evidence linking reactive metabolites and idiosyncratic reactions is circumstantial at best, and in many cases we have virtually no evidence. Furthermore, it is common for a drug to form several reactive metabolites, so it can be difficult to determine which, if any, is responsible for a given idiosyncratic reaction. Although the reactive metabolite hypothesis is logical, it has important implications for drug development, and we need to develop ways to test the hypothesis for specific drugs rigorously. Valid animal models are a powerful tool for testing whether a specific reactive metabolite is responsible for a specific adverse reaction and for studying further the mechanism by which it may induce such reactions; however, such models are rare.