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Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proc Natl Acad Sci U S A

SORA Division, Faculty of Medicine, Sir Alexander Fleming Building, Imperial College London, South Kensington, London, United Kingdom.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 09/2009; 106(34):14728-33. DOI: 10.1073/pnas.0904489106
Source: PubMed

ABSTRACT 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 (1)H 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.

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    • "Multiple omics platforms integrating metabolic changes in the host, including the metabolism of drugs and environmental toxins, with microbiota diversity have highlighted the necessity of personalized medicine. Gut microbial enzymes for the metabolism of commonlyprescribed drugs, such as acetaminophen and cholesterollowering agent simvastatin, were identified [65] [66]. In addition, microbiota plays a critical role in the generation of more-(e.g., sulfasalazine) or less-active (e.g., digoxin) drug metabolites [58]. "
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    • "The gut microbiome (the collective genomes of the gut microbes) encodes 3.3 million non-redundant genes and is 150 times larger than the human gene complement, with most of these genes having unknown functions (Qin et al., 2010). Recent evidences suggested that gut microbiota affect many aspects of host physiology, including the diet, vitamin production, drug metabolism, disease pathogenesis, and the regulation of the immune system (Xu et al., 2013), as well as the metabolism of pharmaceuticals, heavy metals, and organic chemicals (Breton et al., 2013; Clayton et al., 2009). The composition of the gut microbiota and the number of microorganisms differed in dependence on local environmental conditions (Frick and Autenrieth, 2013). "
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