Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism
Clayton, T. Andrew, Baker, David, Lindon, John C., Everett, Jeremy R. and Nicholson, Jeremy K. (2009) Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism. Proceedings of the National Academy of Sciences of the United States of America (PNAS), 106 (34). pp. 14728-14733. ISSN 0027-8424 (Print), 1091-6490 (Online) (doi:10.1073/pnas.0904489106)Full text not available from this repository.
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 redose urinary metabolite profile, and the metabolic fate of a standard dose of the widely used analgesic cetaminophen. Predose and postdose urinary metabolite profiles were determined by 1HNMRspectroscopy. The predose spectra were statistically analyzed in relation to drug etabolite excretion to detect predose biomarkers of drug fate and a human-gut microbiome cometabolite predictor was identified. Thus, we found that individuals having high redose urinary levels of p-cresol sulfate had low postdose urinary ratios of acetaminophen sulfate to acetaminophen lucuronide. We conclude that, in individuals with high acterially mediated p-cresol generation, competitive O-sulfonation of p-cresol reduces the effective systemic apacity 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 ight be deliberately manipulated to improve drug efficacy and to reduce adverse drug reactions.
|Additional Information:|| Published online before print: August 10, 2009.  First published in print: August 25, 2009.  Published as: PNAS, (2009), 106 (34) 14728-14733. This article is freely available online through the PNAS open access option.  Supporting information online at www.pnas.org/cgi/content/full/0904489106/DCSupplemental.|
|Uncontrolled Keywords:||acetaminophen, p-cresol, bacteria, sulfate, glucuronide|
|Subjects:||R Medicine > RS Pharmacy and materia medica|
|Faculty / Department / Research Groups:||Faculty of Engineering & Science > Department of Pharmaceutical, Chemical & Environmental Sciences|
|Last Modified:||08 Dec 2016 14:57|
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