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jlucuixy银虫 (初入文坛)
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By definition, xenobiotic metabolism considers how an organism disposes of a foreign chemical. It is the study of what the body does to the drug. Whether intentional or unintentional, these xenobiotics often have physiological effects. Thus, a major role for biotransformation is to understand how metabolic processes terminate or limit desired physiological effects (efficacy) as well as how other processes may lead to unintended consequences (toxicity). A drug’s duration of action, its intensity of action, and interindividual variability in responsiveness are frequently related to its disposition properties. For drugs with a narrow therapeutic index, these sources of variability can and do lead to adverse effects and may significantly limit the full therapeutic usefulness of the product. Likewise, drug–drug interactions also lead to unintended effects. As an inhibitor or inducer of enzymes involved in the disposition of other co-medications the drug may cause exacerbated pharmacological effects (inhibitors) or therapeutic lapses (inducers). Again, drugs of this nature may have severely restricted use, depending on the therapeutic utility and the co-medication environment in which they would be used. Thus, without even considering how a drug is metabolized, safety can be affected. Dr. James Gillette, the Millers, their coworkers and colleagues, and generations after them have documented how molecular biotransformation leads to toxicity (Brodie et al., 1971; Miller and Miller, 1955). Molecular activation (or biological reactive intermediates) is one of the most intensively studied aspects of both drug metabolism and toxicology. Thousands of publications have documented the breadth of reactions leading to reactive metabolites, and thousands of others have shown the breadth of impact throughout the body and among all species. Consequently, there is a well-developed basis for anticipating structural features that may predispose a molecule to form reactive metabolites. Once discovered, reactive metabolites can often be avoided or minimized by judicious molecular redesign. In fact, both biotransformation scientists and medicinal chemists are obligated to know this area. This knowledge facilitates design of molecules without known liabilities, or at least guides the incorporation of certain worrisome features in a way that can be carefully evaluated. Perhaps because of the well-developed literature linking biotransformation and toxicity, there seems to be a widely held perception that ‘‘most toxicity is due to metabolism.’’ This author does not subscribe to that thesis and will not discuss it further here (Grossman, 2006). However, xenobiotic-induced toxicity is a substantial issue to be dealt with. By most accounts, toxicity is the single most common cause for drug attrition. It is inconceivable that a contemporary pharmaceutical biotransformation scientist will not be involved in toxicityrelated investigations in their career, and probably will be involved many times. However, it is human nature to view everything as a nail if you are a hammer. The most tempting course of action for a biotransformation scientist is to‘‘start with the molecule’’ and posit putative reactive metabolites that could give rise to the observed effects. An alternate approach is to ‘‘start with the lesion’’ and query the pathophysiological drivers that give rise to observed effects. This would include the consideration of unanticipated interactions of the parent molecule or its stable metabolites with any of the 40,000 gene products expressed in the affected organism. Either approach, applied with prudence and substantial good fortune, can yield the answer. With maturity and discipline, the biotransformation scientist learns to dissect toxicology issues through the scientific method, proposing hypotheses and carefully designing experiments to eliminate false hypotheses in a definitive fashion. |
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wypward(金币+2):谢谢新虫，谢谢参与 2010-06-02 17:04:15
jlucuixy(金币+5, 翻译EPI+1): 2010-06-02 19:26:08
jlucuixy(金币+8): 2010-06-04 10:02:56
wypward(金币+2):谢谢新虫，谢谢参与 2010-06-02 17:04:15
jlucuixy(金币+5, 翻译EPI+1): 2010-06-02 19:26:08
jlucuixy(金币+8): 2010-06-04 10:02:56
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定义上，药物代谢是指有机体分解外源化学物质。这是研究机体对药物反应的学科。无论是有意的或是故意的，这些药物对生理都有一定的影响。因此，生物转化的主要方面在于理解代谢过程是如何达到所需的生理影响（药效）或限制在某范围内，以及其他途径会如何带来不期望的后果（毒性）。 药物的作用时间、效果和作用的个人差异性常被认为是其的特性。同样的。不同药物的相互反应也会导致不期望的后果。因为某一药物可能是某种酶的诱导剂或抑制剂，同时作用的药物会因酶被诱导而增效或酶被抑制而减弱药效。再次重申，因为药物的此项特性，药物的使用被治疗机构和共同作用的药物的环境严格的限制。因此，药物的安全性会受到影响，甚至无须考虑药物怎样代谢。 James Gillette博士，Millers和同事们、后辈们建立了分子层面上生物转化导致毒性的档案（Brodie等1971，Miller和Miller1955）。分子激活（或者说生物反应的中间步骤）是药物代谢和毒性研究中最关键的方面之一。上千篇文献证明了激活代谢的许多反应，还有上千篇其他的文献证明了药物对人体及其他物种的广泛影响。因此，有许多成熟的理论基础预测了会引起代谢反应的分子结构特点。一旦发现这些特点，我们就可以通过分子改造避免或最小化这些反应。事实上，生物转化科学家和药物化学科学家均愿意去探索这一领域。这些知识使人们无负担的去改造分子结构，或至少将一些令人担心的特点聚集而能周密的评价。 |
2楼2010-06-02 16:26:43
翻译
jlucuixy(金币+5): 2010-06-03 17:33:54
jlucuixy(金币+7): 2010-06-04 10:03:04
jlucuixy(金币+7): 2010-06-04 10:03:04
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根据定义，异形生物质的新陈代谢研究的是如何使生物体除去异质的化学物质。即是人体对药物反应研究的内容。不管有意或无意，这些生物异源物质往往会产生生理效应。因此，生物转化的主要作用是了解新陈代谢过程是如何终止的，限制理想的生理作用（功效）以及其他过程是如何引起意外后果的（毒性）。药物的持续作用时间，作用强度和人与人之间对药物作用的反应差异通常与药物的属性有关。对于治疗指数小的药物来说，变异性来源能够以及肯定会引起不良反应，甚至会大幅度的限制药物的所有治疗作用。同样的，药物和药物之间的相互作用也会引起意外后果。当抑制剂或酶诱导物卷入其他联合药物治疗的作用时，就会产生恶化的药理反应（抑制剂）或治疗失误（诱导物）。此外，具有这类性质的药物会严格限制使用，使用量取决于药效和它们应用的联合药物治疗环境。因此，即使不考虑药物代谢，安全性也会收到影响。James Gillette医生，the Millers,它们的合作者和同事，以及之后的一代人已经证明了分子生物转化是如何引起毒性的了。分子活化作用（或生物活性中间体）是药物新陈代谢和毒理学最深入的研究方面之一。许多出版物都有记录引起活性代谢物的反应宽度，另有许多记载了人体和其他物种内的反应宽度。因此，这就存在一个良好的基础，可以预见促使分子转化成活性代谢物的物质的结构特性。这些物质一旦被发现，就可以避免产生活性代谢物，或者通过正确的分子重组使之减少。事实上，生物转化学家和药用化学家都有责任研究这个领域。在没有已知负债的情况下，这些知识有助于分子设计，或者至少可以引导某些令人担忧的性能采用一种比较谨慎的评估方式进行合并。也许是因为有大量联系生物转化和毒性的文章，人们还是普遍认为大部分的毒性来源于新陈代谢。本作者并不同意此观点，在此就不进一步讨论(Grossman, 2006)。然而，异形生物质诱发的毒性是一个需要解决的重要问题。大多数人认为，毒性是造成药物消耗的最常见原因。很难想象，一个当代医药生物转化学家在他的职业生涯中会不涉及到与毒性有关的调查研究中，而且很有可能的是会涉及很多次。然而，人类的本性就是，如果你有一把锤子，就会把一切东西看作是钉子。对生物转化学家来说，最具诱惑力的是从分子开始研究，假设活性代谢物能够引起可观测的效应。交替的方法是从病变开始研究，询问引起可观测效应的病理生理学患者。 这将包括对根源分子之间不曾预料的相互作用以及在产生效应的生物体内存在的4000种基因产品的稳定代谢产物的研究。 不管是哪一种方法，谨慎的研究加上充足的好运，就可以获得答案。 通过娴熟的技巧和训练，生物转化学家可以运用科学的方法，仔细分析病理学的问题，提出假设，仔细设计实验明确的剔除错误的假设。 |
3楼2010-06-02 23:15:20
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