Pharmacometabolomics is a rapidly emerging omics science signaling the convergence of clinical pharmacology, metabolomics, precision medicine, and biomarker research. Tuberculosis (TB) treatment outcomes have complex biological, environmental, and social determinants and thus, represent a promising application of pharmacometabolomics. In samples of 23 patients undergoing intensive phase TB therapy for 4 weeks, we identified drug-induced host-metabolome variations before and at repeated time intervals post-treatment: (1) an overall reduction in the oxidative stress levels over the course of TB treatment; (2) a time-dependent induction and inhibition of several enzymes in response to the drugs (CYP2E1, CYP3A4, alcohol dehydrogenase, and aminocarboxymuconate-semialdehyde decarboxylase), and altered oxidative stress levels (aconitase, formylglycine-generating enzyme, α-ketoglutarate dehydrogenase, and succinate-semialdehyde dehydrogenase); (3) an upregulated urea cycle; and (4) altered insulin production. This is the first study of its kind to indicate changes to the host metabolome in response to intensive TB treatment, at different time intervals during the course of treatment. These results provide new insights into the mechanisms of TB drug metabolism, drug action, and drug-related side effects, thereby paving the way for the development of improved therapeutic approaches for the disease, and perhaps more importantly, also for monitoring treatment progression.

中文翻译：

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结核病强化治疗前后尿液代谢组的时间依赖性变化：一项药物代谢组学研究。

药代动力学是一门新兴的组学科学，它标志着临床药理学，代谢组学，精密医学和生物标志物研究的融合。结核病（TB）的治疗结果具有复杂的生物学，环境和社会决定因素，因此代表了药物代谢组学的有希望的应用。在接受TB强化治疗4周的23名患者的样本中，我们确定了药物治疗前和治疗后重复时间间隔的药物诱导的宿主代谢组变化：（1）在TB治疗过程中氧化应激水平总体降低; （2）对药物的几种酶（CYP2E1，CYP3A4，醇脱氢酶和氨基羧基粘康酸酯-半醛脱羧酶）有时间依赖性地诱导和抑制，并改变了氧化应激水平（阿尼卡因酶，甲酰甘氨酸生成酶，α-酮戊二酸脱氢酶和琥珀酸-半醛脱氢酶）；（3）尿素循环上调；（4）胰岛素产生改变。这是同类研究中的第一个，表明在治疗过程中的不同时间间隔，强化结核病治疗后宿主代谢组的变化。这些结果为结核病药物代谢，药物作用和药物相关副作用的机制提供了新的见识，从而为开发改进的疾病治疗方法铺平了道路，也许更重要的是，还为监测治疗进程铺平了道路。这是同类研究中的第一项，表明在治疗过程中的不同时间间隔内，强化结核病治疗后宿主代谢组的变化。这些结果为结核病药物代谢，药物作用和药物相关副作用的机制提供了新的见识，从而为开发改进的疾病治疗方法铺平了道路，也许更重要的是，还为监测治疗进程铺平了道路。这是同类研究中的第一项，表明在治疗过程中的不同时间间隔内，强化结核病治疗后宿主代谢组的变化。这些结果为结核病药物代谢，药物作用和药物相关副作用的机制提供了新的见识，从而为开发改进的疾病治疗方法铺平了道路，也许更重要的是，还为监测治疗进展铺平了道路。