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jlucuixy银虫 (初入文坛)
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[交流]
求助翻译 谢谢了
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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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freshblack
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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