Uetrecht J P
Faculties of Pharmacy and Medicine, University of Toronto, Canada.
Drug Metab Rev. 1992;24(3):299-366. doi: 10.3109/03602539208996297.
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)
有力证据表明，许多药物不良反应，包括特异质药物反应，都涉及活性代谢物。此外，某些易于氧化成活性代谢物的官能团与不良反应的高发生率相关。大多数药物可能都能形成活性代谢物，但体外共价结合的简单比较不太可能准确指示药物引起特异质反应的相对风险，因为它无法表明代谢物在体内的解毒效率。此外，与特定药物相关的不良反应的发生率和性质可能在很大程度上取决于活性代谢物形成的位置以及活性代谢物的化学反应性。这些因素将决定代谢物会与哪些大分子结合，并且已知与某些蛋白质（如白细胞膜中的蛋白质）的共价结合更有可能导致免疫介导的反应或其他类型的毒性。一些活性代谢物，如酰基葡萄糖醛酸，可自由循环并可能在几乎任何器官中引发不良反应；然而，大多数活性代谢物的生物半衰期较短，尽管少量可能会从其形成的器官中逸出，但这些代谢物不太可能达到足以在其他器官中引起毒性的浓度。许多特异质药物反应涉及白细胞，尤其是粒细胞缺乏症和药物性狼疮。我们和其他人已经证明，药物可被活化的中性粒细胞和单核细胞代谢为活性代谢物。主要反应似乎是与白细胞产生的次氯酸反应。次氯酸具有很强的反应性，因此很可能会发现许多其他药物也会被活化的白细胞代谢。一些中性粒细胞前体含有髓过氧化物酶和NADPH氧化酶系统，这些细胞也可能氧化药物。因此，虽然没有直接证据，但合理推测活化的白细胞或骨髓中的中性粒细胞前体产生的活性代谢物可能是药物性粒细胞缺乏症和再生障碍性贫血的原因。这可能涉及直接毒性或免疫介导的反应。这些机制并非相互排斥，甚至在同一患者中，两种机制都可能导致毒性。在药物性狼疮中，关于狼疮的一个普遍假说是II类MHC抗原的修饰。（摘要截于400字）
