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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism
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Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism

机译：影响人体药物代谢的重要宿主-微生物组代谢相互作用的药物代谢组学鉴定

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摘要

We provide a demonstration in humans of the principle of pharmaco-metabonomics 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 ~1H 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 microbiome activity 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.
机译：我们通过显示个体的代谢表型（以服药前尿代谢产物谱的形式）与标准剂量的广泛使用的止痛药对乙酰氨基酚的代谢结局之间的明确联系，来向人们证明药物代谢组学的原理。剂量前和剂量后尿代谢物谱通过〜1 H NMR谱确定。对与药物代谢产物排泄有关的前药频谱进行统计分析，以检测前药生物命运的生物标志物，并鉴定了人肠道微生物组代谢物预测物。因此，我们发现具有高剂量前尿中对甲酚硫酸盐水平的个体具有低剂量的硫酸对乙酰氨基酚与对乙酰氨基酚葡糖苷酸的尿后比率。我们得出结论，在具有高细菌介导的对甲酚生成能力的个体中，对甲酚的竞争性O磺化作用会降低磺化对乙酰氨基酚的有效全身能力。鉴于对乙酰氨基酚是一种如此广泛使用且看似易于理解的药物，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。但是，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，并且我们的发现对某些疾病以及由许多不同药物和异源生物诱导的可变反应也具有重要意义。我们建议评估微生物组活性的影响应该是药物开发和个性化保健的组成部分。此外，我们设想可以故意操纵肠道细菌种群以提高药物疗效并减少药物不良反应。

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    T. Andrew Clayton; David Baker; John C. Lindon; Jeremy R. Everett; Jeremy K. Nicholson;

  • 作者单位

    Biomolecular Medicine, SORA Division, Faculty of Medicine, Sir Alexander Fleming Building, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom;

    Pfizer Inc., 50 Pequot Avenue, New London, CT 06320;

    Biomolecular Medicine, SORA Division, Faculty of Medicine, Sir Alexander Fleming Building, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom;

    Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom;

    Biomolecular Medicine, SORA Division, Faculty of Medicine, Sir Alexander Fleming Building, Imperial College London, South Kensington, London SW7 2AZ, United Kingdom;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    acetaminophen; p-cresol; bacteria; sulfate; glucuronide;

    机译：对乙酰氨基酚;对甲酚菌;硫酸盐葡糖醛酸;

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