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Pharmaco-metabonomic phenotyping and personalized drug treatment.

机译：药物代谢组学表型和个性化药物治疗。

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There is a clear case for drug treatments to be selected according to the characteristics of an individual patient, in order to improve efficacy and reduce the number and severity of adverse drug reactions. However, such personalization of drug treatments requires the ability to predict how different individuals will respond to a particular drug/dose combination. After initial optimism, there is increasing recognition of the limitations of the pharmacogenomic approach, which does not take account of important environmental influences on drug absorption, distribution, metabolism and excretion. For instance, a major factor underlying inter-individual variation in drug effects is variation in metabolic phenotype, which is influenced not only by genotype but also by environmental factors such as nutritional status, the gut microbiota, age, disease and the co- or pre-administration of other drugs. Thus, although genetic variation is clearly important, it seems unlikely that personalized drug therapy will beenabled for a wide range of major diseases using genomic knowledge alone. Here we describe an alternative and conceptually new 'pharmaco-metabonomic' approach to personalizing drug treatment, which uses a combination of pre-dose metabolite profiling and chemometrics to model and predict the responses of individual subjects. We provide proof-of-principle for this new approach, which is sensitive to both genetic and environmental influences, with a study of paracetamol (acetaminophen) administered to rats. We show pre-dose prediction of an aspect of the urinary drug metabolite profile and an association between pre-dose urinary composition and the extent of liver damage sustained after paracetamol administration.
机译：为了提高疗效并减少药物不良反应的数量和严重性，显然有根据个别患者的特征选择药物治疗的情况。然而，这种药物治疗的个性化要求能够预测不同的个体对特定药物/剂量组合的反应。经过最初的乐观之后，人们越来越认识到药物基因组学方法的局限性，这种局限性没有考虑到环境对药物吸收，分布，代谢和排泄的重要影响。例如，个体间药物作用差异的主要因素是代谢表型的变化，这不仅受基因型的影响，还受环境因素（如营养状况，肠道菌群，年龄，疾病，共同或未受感染）的影响。 -其他药物的管理。因此，尽管遗传变异显然很重要，但仅通过基因组知识就不可能针对多种主要疾病启用个性化药物治疗。在这里，我们描述了个性化药物治疗的另一种概念上新的“药物代谢组学”方法，该方法结合了剂量前代谢物谱分析和化学计量学来建模和预测个体受试者的反应。我们通过对大鼠对乙酰氨基酚（对乙酰氨基酚）的研究，为这种对遗传和环境影响均敏感的新方法提供了原理证明。我们显示了尿中药物代谢产物概况的一个方面的剂量前预测以及剂量前尿液成分与对乙酰氨基酚给药后持续肝损害程度之间的关联。

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