Division of Clinical Pharmacology, Department of Medicine, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa.
ACS Infect Dis. 2020 Mar 13;6(3):459-466. doi: 10.1021/acsinfecdis.9b00405. Epub 2020 Feb 3.
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.
先前已经证实，在啮齿动物体内，夫西地酸（FA）会迅速代谢为其 C-3 差向异构体，其抗分枝杆菌活性明显低于 FA。这在一定程度上解释了 FA 在结核分枝杆菌感染的小鼠模型中尽管具有很强的体外抗分枝杆菌活性，但体内疗效却不佳的原因。在目前的研究中，我们假设 FA 的 C-3 烷基酯前药能够提供更高水平的药物，并防止 FA 以其原始形式给药时观察到的快速代谢。FA 及其 3-酮夫西地酸代谢物以及 FA 的新型 C-3 烷基酯前药的药代动力学分析表明，由于快速代谢为一种种属特异性代谢物 3-表夫西地酸，FA 在小鼠体内的暴露水平较低。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 FA C-3 酯前药提高药物浓度和组织分布的最初目标。
