摘要
某些特殊的药物不良反应(IADRs)可以由药物代谢过程中形成的亲电蛋白反应代谢物引发。虽然一些方法(如在药物设计中结构预警概念,谷胱甘肽(GSH)捕获,蛋白质共价结合)对于研究活性代谢物的组成是可行的,但是应用这些参数来预测IADR潜在性仍然是一个重大挑战。目前工作趋势是与苯胺结构警报相关的毒性检查,在2011年的前200名处方药和最近批准(2009 - 2013)的小分子药物,有30 个以苯胺结构为基础的药物撤出商业使用或IADRs的黑箱警告。在一些有毒的药物、最常用的处方药、最近批准的一类药物中可发现苯胺的子结构。来源于苯胺生物活化的活性代谢物也在这三类药物中被提及用于比较。在最常用处方列表中,毒性药品和绝大多数药物之间的主要区别在于一天的剂量多少,最经常发生特殊药物不良反应的药物一般具有很高的每日剂量(超过数百毫克)。特殊药物不良反应有时需要更大的耐受性,如某些药物用于治疗罕见、未满足的医疗需求(如癌症)。总体而言,分析表明优化的药理药效和药物动力学将导致剂量降低。因此,怎样使母体药物/代谢物给身体带来更低的负担应在药物研发中考虑。
关键词: 药物不良反应,苯胺,药物,细胞色素P450,谷胱甘肽,特殊的,活性代谢物
Current Medicinal Chemistry
Title:Should the Incorporation of Structural Alerts be Restricted in Drug Design? An Analysis of Structure-Toxicity Trends with Aniline-Based Drugs
Volume: 22 Issue: 4
Author(s): A.S. Kalgutkar
Affiliation:
关键词: 药物不良反应,苯胺,药物,细胞色素P450,谷胱甘肽,特殊的,活性代谢物
摘要: Certain idiosyncratic adverse drug reactions (IADRs) can be triggered by electrophilic protein-reactive metabolites that are formed in the process of drug metabolism. While methodologies (e.g., structural alert concept in drug design, glutathione (GSH) trapping, and protein covalent binding) for examining reactive metabolite (RM) formation are available, predicting the IADR potential applying these parameters remains a significant challenge. The present work examines toxicity trends associated with the aniline structural alert in the top 200 prescribed drugs of 2011 and recently approved (2009-2013) small molecule drugs, in relation with 30 aniline-based drugs withdrawn from commercial use or associated with a black box warning for IADRs. The aniline sub-structure was found in several drugs from the toxic, mostprescribed, and recently approved category. RMs resulting from the bioactivation of the aniline alert was also noted in the three categories chosen for comparison. A major discriminator between the toxic drugs and the majority of drugs in the most-prescribed list, however, was the daily dose – drugs most frequented associated with IADRs were the ones with higher daily doses (exceeding hundreds of milligrams). A greater tolerance for IADRs was also noted with certain drugs intended to treat rare, unmet medical needs (e.g., cancer). Overall, the analysis suggests that optimization of pharmacologic potency and pharmacokinetics that would lead to a lower daily dose, and therefore, a lower body burden of parent drug/metabolites, should be taken into consideration in drug discovery.
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A.S. Kalgutkar , Should the Incorporation of Structural Alerts be Restricted in Drug Design? An Analysis of Structure-Toxicity Trends with Aniline-Based Drugs, Current Medicinal Chemistry 2015; 22 (4) . https://dx.doi.org/10.2174/0929867321666141112122118
DOI https://dx.doi.org/10.2174/0929867321666141112122118 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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