Methemoglobin formation by hydroxylamine metabolites of sulfamethoxazole and dapsone: implications for differences in adverse drug reactions.
Methemoglobin formation by hydroxylamine metabolites of sulfamethoxazole and dapsone: implications for differences in adverse drug reactions.
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发表时间：
1999-03
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通讯作者：
T. Reilly;P. Woster;C. Svensson
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作者：
T. Reilly;P. Woster;C. Svensson
甲氧苄啶-磺胺甲恶唑和氨苯砜的药物不良反应发生率的差异可能是由于其羟胺代谢产物的形成、处置、毒性和/或解毒的差异。在这项研究中，我们研究是否在红细胞[红细胞（RBC）]的磺胺甲恶唑羟胺（SMX-NOH）和氨苯砜羟胺（DDS-NOH）的生化处理的差异有助于这种差异的发病率。高铁血红蛋白（MetHgb）的形成能力的两种代谢产物进行了比较后，60分钟的孵育洗涤红细胞从四个健康的人类志愿者。DDS-NOH在形成MetHgb的能力方面显著更有效（P =.004），但与SMX-NOH同样有效。通过裂解RBC消除处置中的潜在差异不会改变任一羟胺的MetHgb形成效力。在与DDS-NOH相关的浓度下，DDS-NOH对母体胺的还原更大。MetHgb形成效力的维持依赖于谷胱甘肽的再循环，但在DDS-NOH和SMX-NOH之间没有观察到循环效率的差异。与此相反，羟胺诱导MetHgb形成的药效学没有改变预处理与葡萄糖6-磷酸脱氢酶抑制剂表雄酮或化合物，改变正常的抗氧化酶活性。亚甲蓝，刺激NADPH依赖性MetHgb还原酶活性，降低MetHgb水平，但没有改变这些羟胺的差异效力。当与纯化的人血红蛋白A0孵育时，DDS-NOH也显著更有效。总的来说，这些数据表明，固有的更大的反应性DDS-NOH与血红蛋白，更大的转换DDS-NOH其母体胺，和潜在的差异，处置羟胺代谢物可能有助于优先发展的氨苯砜诱导的血液毒性和磺胺甲恶唑诱导的超敏反应。
Differences in the incidence of adverse drug reactions to trimethoprim-sulfamethoxazole and dapsone may result from differences in the formation, disposition, toxicity, and/or detoxification of their hydroxylamine metabolites. In this study, we examine whether differences in the biochemical processing of sulfamethoxazole hydroxylamine (SMX-NOH) and dapsone hydroxylamine (DDS-NOH) by erythrocytes [red blood cells (RBCs)] contribute to this differential incidence. The methemoglobin (MetHgb)-forming capacity of both metabolites was compared after a 60-min incubation with washed RBCs from four healthy human volunteers. DDS-NOH was significantly more potent (P =.004) but equally efficacious with SMX-NOH in its ability to form MetHgb. The elimination of potential differences in disposition by lysing RBCs did not change the MetHgb-forming potency of either hydroxylamine. At pharmacologically relevant concentrations, greater reduction to the parent amine occurred with DDS-NOH. Maintenance of MetHgb-forming potency was dependent on recycling with glutathione, but no difference in cycling efficiency was observed between DDS-NOH and SMX-NOH. In contrast, the pharmacodynamics of hydroxylamine-induced MetHgb formation were not changed by pretreatment with the glucose 6-phosphate dehydrogenase inhibitor epiandrosterone or by compounds that alter normal antioxidant enzyme activity. Methylene blue, which stimulates NADPH-dependent MetHgb reductase activity, decreased MetHgb levels but did not alter the differential potency of these hydroxylamines. DDS-NOH was also significantly more potent when incubated with purified human hemoglobin A0. Collectively, these data suggest that the inherently greater reactivity of DDS-NOH with hemoglobin, the greater conversion of DDS-NOH to its parent amine, and potential differences in disposition of hydroxylamine metabolites may contribute to the preferential development of dapsone-induced hemotoxicity and sulfamethoxazole-induced hypersensitivity reactions.