Is it possible to more accurately predict which drug candidates will cause idiosyncratic drug reactions?
Is it possible to more accurately predict which drug candidates will cause idiosyncratic drug reactions?
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是否可以更准确地预测哪些候选药物会引起特殊药物反应？
DOI：
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发表时间：
2000
影响因子：
2.3
通讯作者：
Jack Uetrecht
中科院分区：
文献类型：
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作者：
Jack Uetrecht
在后期临床试验期间或药物已发布后意外发生特异质药物反应可能导致其使用受到严重限制或无法发布/撤回。这导致了药物开发中相当大的不确定性，并导致试图预测药物引起此类反应的潜力。似乎大多数特异质药物反应是由于反应性代谢物引起的;然而，许多形成反应性代谢物的药物与特异质药物反应的发生率非常低相关。因此。筛选药物产生活性代谢物的能力可能会导致许多好的候选药物被拒绝。有证据表明，如果存在某种“危险信号”，则更有可能发生特异质药物反应。因此，引起一定程度的细胞应激或损伤的药物可能更有可能导致特异质药物反应的高发生率。推定的危险信号的确切性质尚不清楚。然而，使用表达基因组学和蛋白质组学对已知与特异质反应高发生率相关的药物的作用进行筛选，可以揭示mRNA和蛋白质表达的一种或多种模式，从而预测哪些药物将导致特异质药物反应的高发生率。虽然特异质药物反应通常不会在动物试验中检测到，因为它们在动物中的特异质与在人类中的一样，但药物反应性代谢产物也可能在动物中引起类似的细胞应激。更有可能的是，在大多数情况下，对反应性代谢物的免疫应答差异决定了哪些个体会发生特异质反应。如果用候选药物治疗的动物中某些蛋白质的表达可以用作筛选方法来预测药物引起特异质药物反应的高发生率的潜力，这将极大地促进更安全药物的开发。
The unexpected occurrence of idiosyncratic drug reactions during late clinical trials or after a drug has been released can lead to a severe restriction in its use or failure to release/withdrawal. This leads to considerable uncertainty in drug development and has led to attempts to try to predict a drug's potential to cause such reactions. It appears that most idiosyncratic drug reactions are due to reactive metabolites; however, many drugs that form reactive metabolites are associated with a very low incidence of idiosyncratic drug reactions. Therefore. screening drug for their ability to generate reactive metabolites is likely to cause the rejection of many good drug candidates. There is evidence to suggest that an idiosyncratic drug reaction is more likely if there is some "danger signal'. Thus drugs that cause some degree of cell stress or damage may be more likely to lead to a high incidence of idiosyncratic drug reactions. The exact nature of the putative danger signals is unknown. However, a screen of the effects of drugs known to be associated with a high incidence of idiosyncatic reactions using expression genomics and proteomics may reveal a pattern or patterns of mRNA and protein expression that predict which drugs will cause a high incidence of idiosyncratic drug reactions. Although idiosyncratic drug reactions are not usually detected in animal tests because they are just as idiosyncratic in animals as they are in humans, it is likely that drug reactive metabolites would also cause similar cell stress in animals. It is more likely that in most cases it is differences in the immune response to the reactive metabolites that determine which individuals will develop an idiosyncratic reaction. If the expression of certain proteins in animals treated with a drug candidate could be used as a screening method to predict a drug's potential to cause a high incidence of idiosyncratic drug reactions, it would greatly facilitate the development of safer drugs.