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jlucuixy銀蟲 (初入文壇)
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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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feihongjia
新蟲 (初入文壇)
- 應(yīng)助: 0 (幼兒園)
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翻譯
jlucuixy(金幣+5): 2010-06-03 17:33:54
jlucuixy(金幣+7): 2010-06-04 10:03:04
jlucuixy(金幣+7): 2010-06-04 10:03:04
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根據(jù)定義，異形生物質(zhì)的新陳代謝研究的是如何使生物體除去異質(zhì)的化學(xué)物質(zhì)。即是人體對藥物反應(yīng)研究的內(nèi)容。不管有意或無意，這些生物異源物質(zhì)往往會產(chǎn)生生理效應(yīng)。因此，生物轉(zhuǎn)化的主要作用是了解新陳代謝過程是如何終止的，限制理想的生理作用（功效）以及其他過程是如何引起意外后果的（毒性）。藥物的持續(xù)作用時間，作用強度和人與人之間對藥物作用的反應(yīng)差異通常與藥物的屬性有關(guān)。對于治療指數(shù)小的藥物來說，變異性來源能夠以及肯定會引起不良反應(yīng)，甚至?xí)蠓鹊南拗扑幬锏乃兄委熥饔�。同樣的，藥物和藥物之間的相互作用也會引起意外后果。當(dāng)抑制劑或酶誘導(dǎo)物卷入其他聯(lián)合藥物治療的作用時，就會產(chǎn)生惡化的藥理反應(yīng)（抑制劑）或治療失誤（誘導(dǎo)物）。此外，具有這類性質(zhì)的藥物會嚴(yán)格限制使用，使用量取決于藥效和它們應(yīng)用的聯(lián)合藥物治療環(huán)境。因此，即使不考慮藥物代謝，安全性也會收到影響。James Gillette醫(yī)生，the Millers,它們的合作者和同事，以及之后的一代人已經(jīng)證明了分子生物轉(zhuǎn)化是如何引起毒性的了。分子活化作用（或生物活性中間體）是藥物新陳代謝和毒理學(xué)最深入的研究方面之一。許多出版物都有記錄引起活性代謝物的反應(yīng)寬度，另有許多記載了人體和其他物種內(nèi)的反應(yīng)寬度。因此，這就存在一個良好的基礎(chǔ)，可以預(yù)見促使分子轉(zhuǎn)化成活性代謝物的物質(zhì)的結(jié)構(gòu)特性。這些物質(zhì)一旦被發(fā)現(xiàn)，就可以避免產(chǎn)生活性代謝物，或者通過正確的分子重組使之減少。事實上，生物轉(zhuǎn)化學(xué)家和藥用化學(xué)家都有責(zé)任研究這個領(lǐng)域。在沒有已知負(fù)債的情況下，這些知識有助于分子設(shè)計，或者至少可以引導(dǎo)某些令人擔(dān)憂的性能采用一種比較謹(jǐn)慎的評估方式進行合并。也許是因為有大量聯(lián)系生物轉(zhuǎn)化和毒性的文章，人們還是普遍認(rèn)為大部分的毒性來源于新陳代謝。本作者并不同意此觀點，在此就不進一步討論(Grossman, 2006)。然而，異形生物質(zhì)誘發(fā)的毒性是一個需要解決的重要問題。大多數(shù)人認(rèn)為，毒性是造成藥物消耗的最常見原因。很難想象，一個當(dāng)代醫(yī)藥生物轉(zhuǎn)化學(xué)家在他的職業(yè)生涯中會不涉及到與毒性有關(guān)的調(diào)查研究中，而且很有可能的是會涉及很多次。然而，人類的本性就是，如果你有一把錘子，就會把一切東西看作是釘子。對生物轉(zhuǎn)化學(xué)家來說，最具誘惑力的是從分子開始研究，假設(shè)活性代謝物能夠引起可觀測的效應(yīng)。交替的方法是從病變開始研究，詢問引起可觀測效應(yīng)的病理生理學(xué)患者。 這將包括對根源分子之間不曾預(yù)料的相互作用以及在產(chǎn)生效應(yīng)的生物體內(nèi)存在的4000種基因產(chǎn)品的穩(wěn)定代謝產(chǎn)物的研究。 不管是哪一種方法，謹(jǐn)慎的研究加上充足的好運，就可以獲得答案。 通過嫻熟的技巧和訓(xùn)練，生物轉(zhuǎn)化學(xué)家可以運用科學(xué)的方法，仔細(xì)分析病理學(xué)的問題，提出假設(shè)，仔細(xì)設(shè)計實驗明確的剔除錯誤的假設(shè)。 |
3樓2010-06-02 23:15:20
freshblack
金蟲 (正式寫手)
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★ ★
wypward(金幣+2):謝謝新蟲，謝謝參與 2010-06-02 17:04:15
jlucuixy(金幣+5, 翻譯EPI+1): 2010-06-02 19:26:08
jlucuixy(金幣+8): 2010-06-04 10:02:56
wypward(金幣+2):謝謝新蟲，謝謝參與 2010-06-02 17:04:15
jlucuixy(金幣+5, 翻譯EPI+1): 2010-06-02 19:26:08
jlucuixy(金幣+8): 2010-06-04 10:02:56
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定義上，藥物代謝是指有機體分解外源化學(xué)物質(zhì)。這是研究機體對藥物反應(yīng)的學(xué)科。無論是有意的或是故意的，這些藥物對生理都有一定的影響。因此，生物轉(zhuǎn)化的主要方面在于理解代謝過程是如何達到所需的生理影響（藥效）或限制在某范圍內(nèi)，以及其他途徑會如何帶來不期望的后果（毒性）。 藥物的作用時間、效果和作用的個人差異性常被認(rèn)為是其的特性。同樣的。不同藥物的相互反應(yīng)也會導(dǎo)致不期望的后果。因為某一藥物可能是某種酶的誘導(dǎo)劑或抑制劑，同時作用的藥物會因酶被誘導(dǎo)而增效或酶被抑制而減弱藥效。再次重申，因為藥物的此項特性，藥物的使用被治療機構(gòu)和共同作用的藥物的環(huán)境嚴(yán)格的限制。因此，藥物的安全性會受到影響，甚至無須考慮藥物怎樣代謝。 James Gillette博士，Millers和同事們、后輩們建立了分子層面上生物轉(zhuǎn)化導(dǎo)致毒性的檔案（Brodie等1971，Miller和Miller1955）。分子激活（或者說生物反應(yīng)的中間步驟）是藥物代謝和毒性研究中最關(guān)鍵的方面之一。上千篇文獻證明了激活代謝的許多反應(yīng)，還有上千篇其他的文獻證明了藥物對人體及其他物種的廣泛影響。因此，有許多成熟的理論基礎(chǔ)預(yù)測了會引起代謝反應(yīng)的分子結(jié)構(gòu)特點。一旦發(fā)現(xiàn)這些特點，我們就可以通過分子改造避免或最小化這些反應(yīng)。事實上，生物轉(zhuǎn)化科學(xué)家和藥物化學(xué)科學(xué)家均愿意去探索這一領(lǐng)域。這些知識使人們無負(fù)擔(dān)的去改造分子結(jié)構(gòu)，或至少將一些令人擔(dān)心的特點聚集而能周密的評價。 |
2樓2010-06-02 16:26:43
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