Dual mechanisms suppress meloxicam bioactivation relative to sudoxicam.
Dual mechanisms suppress meloxicam bioactivation relative to sudoxicam.
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DOI：
10.1016/j.tox.2020.152478
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发表时间：
2020-07
期刊：
影响因子：
4.5
通讯作者：
Miller GP
中科院分区：
文献类型：
--
作者：
Barnette DA;Schleiff MA;Osborn LR;Flynn N;Matlock M;Swamidass SJ;Miller GP
噻唑类化合物是广泛存在于天然产物和药物中的生物活性芳香族杂环化合物。这些分子通常经过无害的消除；然而，由于噻唑的多步骤生物活化产生活性硫酰胺，可能会发生肝毒性反应。这些结果差异的基础仍不清楚。一个典型的例子是观察到的舒多昔康的高肝脏毒性，与美洛昔康的相对安全使用和商品化形成对比，美洛昔康在结构上与舒多昔康不同，只添加了一个甲基。这两种药物都经历了生物激活，但美洛昔康由于甲基的羟基化而表现出额外的解毒途径。我们假设，由于甲基是弱电子供体，噻唑生物活化效率在舒多昔康和美洛昔康中是相似的，因此，生物活化的相关性取决于竞争解毒途径。为了快速分析，我们模拟了舒多昔康衍生物的环氧化反应，以考察取代基对噻唑生物活性的影响。正如预期的那样，给电子基团增加了环氧化的可能性，而对甲基的影响最小，但模型预测在所有类型的取代基中并不能很好地推断。通过分析方法，我们测量了舒多昔康和美洛昔康在人肝微粒体中代谢激活的稳态动力学。苏洛昔康的生物活化效率是美洛昔康的6倍，而美洛昔康的解毒效率是生物活化的6倍。总体而言，考虑到所有代谢清除途径，舒多昔康生物激活的可能性是美洛昔康的15倍。根据表型研究，动力学差异可能源于不同的酶催化不同的代谢途径。美洛昔康甲基不是简单地提供另一种解毒途径，而是抑制了生物激活反应。这些发现表明，噻唑取代基对生物活性的影响比之前认为的要复杂得多，可能导致其毒性潜力的不可预测性。
Thiazoles are biologically active aromatic heterocyclic rings occurring frequently in natural products and drugs. These molecules undergo typically harmless elimination; however, a hepatotoxic response can occur due to multistep bioactivation of the thiazole to generate a reactive thioamide. A basis for those differences in outcomes remains unknown. A textbook example is the high hepatotoxicity observed for sudoxicam in contrast to the relative safe use and marketability of meloxicam, which differs in structure from sudoxicam by the addition of a single methyl group. Both drugs undergo bioactivation, but meloxicam exhibits an additional detoxification pathway due to hydroxylation of the methyl group. We hypothesized that thiazole bioactivation efficiency is similar between sudoxicam and meloxicam due to the methyl group being a weak electron donator, and thus, the relevance of bioactivation depends on the competing detoxification pathway. For a rapid analysis, we modeled epoxidation of sudoxicam derivatives to investigate the impact of substituents on thiazole bioactivation. As expected, electron donating groups increased the likelihood for epoxidation with a minimal effect for the methyl group, but model predictions did not extrapolate well among all types of substituents. Through analytical methods, we measured steady-state kinetics for metabolic bioactivation of sudoxicam and meloxicam by human liver microsomes. Sudoxicam bioactivation was 6-fold more efficient than that for meloxicam, yet meloxicam showed a 6-fold higher efficiency of detoxification than bioactivation. Overall, sudoxicam bioactivation was 15-fold more likely than meloxicam considering all metabolic clearance pathways. Kinetic differences likely arise from different enzymes catalyzing respective metabolic pathways based on phenotyping studies. Rather than simply providing an alternative detoxification pathway, the meloxicam methyl group suppressed the bioactivation reaction. These findings indicate the impact of thiazole substituents on bioactivation is more complex than previously thought and likely contributes to the unpredictability of their toxic potential.
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