Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism
Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism
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DOI：
10.1073/pnas.0904489106
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发表时间：
2009-08-25
影响因子：
11.1
通讯作者：
Nicholson, Jeremy K.
中科院分区：
文献类型：
--
作者：
Clayton, T. Andrew;Baker, David;Nicholson, Jeremy K.
我们提供了一个演示在人类的药物代谢组学的原则，通过显示一个明确的个人的代谢表型之间的连接，在给药前尿代谢产物的形式，和广泛使用的止痛剂对乙酰氨基酚的标准剂量的代谢命运。通过H-1 NMR光谱法测定给药前和给药后尿液代谢产物谱。对给药前光谱与药物代谢物排泄的关系进行统计分析，以检测药物结局的给药前生物标志物，并确定了人肠道微生物组共代谢物预测因子。因此，我们发现给药前尿液中硫酸对甲酚水平较高的个体给药后尿液中硫酸对乙酰氨基酚与对乙酰氨基酚葡糖苷酸的比值较低。我们的结论是，在高细菌介导的对甲酚产生的个人，竞争性的对甲酚O-磺化降低了有效的系统能力磺化对乙酰氨基酚。鉴于对乙酰氨基酚是一种广泛使用且似乎很好理解的药物，这一发现清楚地证明了药物代谢组学方法的巨大潜力和力量。然而，我们预计许多其他磺化反应也会受到与对甲酚竞争的类似影响，我们的发现对某些疾病以及许多不同药物和外源性物质诱导的可变反应也具有重要影响。我们建议，评估微生物活性的影响应该是药物开发和个性化医疗保健的一个组成部分。此外，我们设想可能会故意操纵肠道细菌种群，以提高药物功效并减少药物不良反应。
We provide a demonstration in humans of the principle of pharmacometabonomics by showing a clear connection between an individual's metabolic phenotype, in the form of a predose urinary metabolite profile, and the metabolic fate of a standard dose of the widely used analgesic acetaminophen. Predose and postdose urinary metabolite profiles were determined by H-1 NMR spectroscopy. The predose spectra were statistically analyzed in relation to drug metabolite excretion to detect predose biomarkers of drug fate and a human-gut microbiome cometabolite predictor was identified. Thus, we found that individuals having high predose urinary levels of p-cresol sulfate had low postdose urinary ratios of acetaminophen sulfate to acetaminophen glucuronide. We conclude that, in individuals with high bacterially mediated p-cresol generation, competitive O-sulfonation of p-cresol reduces the effective systemic capacity to sulfonate acetaminophen. Given that acetaminophen is such a widely used and seemingly well-understood drug, this finding provides a clear demonstration of the immense potential and power of the pharmacometabonomic approach. However, we expect many other sulfonation reactions to be similarly affected by competition with p-cresol and our finding also has important implications for certain diseases as well as for the variable responses induced by many different drugs and xenobiotics. We propose that assessing the effects of microbiomeactivity should be an integral part of pharmaceutical development and of personalized health care. Furthermore, we envisage that gut bacterial populations might be deliberately manipulated to improve drug efficacy and to reduce adverse drug reactions.