Fusidic acid (FA) has previously been shown to be rapidly metabolized in rodents to its C-3 epimer, which has significantly lower antimycobacterial activity relative to FA. This was in part hypothesized to account for FA's lack of in vivo efficacy in a mouse model of tuberculosis despite potent in vitro antimycobacterial activity. In the current work, we hypothesized that C-3 alkyl ester prodrugs of FA would deliver higher levels of the drug and prevent the rapid metabolism observed upon administration of FA in its original form. Pharmacokinetic analysis of FA and its 3-ketofusidic acid metabolite as well as novel C-3 alkyl ester prodrugs of FA revealed that FA has low exposure in mice due to rapid metabolism to a species-specific metabolite, 3-epifusidic acid. The C-3 alkyl ester prodrugs showed improved absorption and tissue distribution in pharmacokinetic and organ distribution experiments. These results support the original objective of the FA C-3 ester prodrugs to improve drug concentrations and tissue distribution.

中文翻译：

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C-3烷基酯作为夫西地酸的潜在抗分枝杆菌前药的药代动力学和器官分布。

梭链孢酸（FA）先前已显示在啮齿动物中快速代谢为其C-3差向异构体，其相对于FA具有明显较低的抗分枝杆菌活性。尽管有很强的体外抗分枝杆菌活性，但部分假设是由于FA在结核病小鼠模型中缺乏体内功效。在当前的工作中，我们假设FA的C-3烷基酯前药将提供更高水平的药物，并阻止以原始形式施用FA时观察到的快速代谢。对FA及其3-酮夫西迪酸代谢产物以及FA的新型C-3烷基酯前药的药代动力学分析表明，FA在小鼠中具有较低的暴露度，这是由于其能快速代谢为一种特定于物种的代谢物3-表观吡啶酸。C-3烷基酯前药在药代动力学和器官分布实验中显示出改善的吸收和组织分布。这些结果支持了FA C-3酯前药改善药物浓度和组织分布的最初目标。