Idiosyncratic drug reactions are a significant cause of morbidity and mortality for patients; they also markedly increase the uncertainty of drug development. The major targets are skin, liver, and bone marrow. Clinical characteristics suggest that IDRs are immune mediated, and there is substantive evidence that most, but not all, IDRs are caused by chemically reactive species. However, rigorous mechanistic studies are very difficult to perform, especially in the absence of valid animal models. Models to explain how drugs or reactive metabolites interact with the MHC/T-cell receptor complex include the hapten and P-I models, and most recently it was found that abacavir can interact reversibly with MHC to alter the endogenous peptides that are presented to T cells. The discovery of HLA molecules as important risk factors for some IDRs has also significantly contributed to our understanding of these adverse reactions, but it is not yet clear what fraction of IDRs have a strong HLA dependence. In addition, with the exception of abacavir, most patients who have the HLA that confers a higher IDR risk with a specific drug will not have an IDR when treated with that drug. Interindividual differences in T-cell receptors and other factors also presumably play a role in determining which patients will have an IDR. The immune response represents a delicate balance, and immune tolerance may be the dominant response to a drug that can cause IDRs.

中文翻译：

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异质性药物不良反应：当前概念。

异质性药物反应是患者发病和死亡的重要原因；它们也显着增加了药物开发的不确定性。主要目标是皮肤、肝脏和骨髓。临床特征表明 IDR 是免疫介导的，并且有大量证据表明，大多数（但不是全部）IDR 是由化学反应性物质引起的。然而，严格的机械研究很难进行，尤其是在没有有效的动物模型的情况下。解释药物或反应性代谢物如何与 MHC/T 细胞受体复合物相互作用的模型包括半抗原和 PI 模型，最近发现阿巴卡韦可以与 MHC 可逆地相互作用以改变呈递给 T 细胞的内源性肽。HLA 分子作为一些 IDR 的重要风险因素的发现也极大地促进了我们对这些不良反应的理解，但目前尚不清楚 IDR 中有多少部分具有强烈的 HLA 依赖性。此外，除阿巴卡韦外，大多数患有 HLA 的患者使用特定药物会导致更高的 IDR 风险，在使用该药物治疗时不会出现 IDR。T 细胞受体和其他因素的个体差异也可能在确定哪些患者会出现 IDR 方面发挥作用。免疫反应代表了一种微妙的平衡，免疫耐受可能是对可引起 IDR 的药物的主要反应。除阿巴卡韦外，大多数患有 HLA 且使用特定药物导致 IDR 风险较高的患者在使用该药物治疗时不会出现 IDR。T 细胞受体和其他因素的个体差异也可能在确定哪些患者会出现 IDR 方面发挥作用。免疫反应代表了一种微妙的平衡，免疫耐受可能是对可引起 IDR 的药物的主要反应。除阿巴卡韦外，大多数患有 HLA 且使用特定药物导致 IDR 风险较高的患者在使用该药物治疗时不会出现 IDR。T 细胞受体和其他因素的个体差异也可能在确定哪些患者会出现 IDR 方面发挥作用。免疫反应代表了一种微妙的平衡，免疫耐受可能是对可引起 IDR 的药物的主要反应。