Cited by 824Pharmacogenetics and Drug MetabolismMetabolomics and Mass Spectrometry StudiesDrug-Induced Hepatotoxicity and Protection

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Pharmaco-metabonomic phenotyping and personalized drug treatment

Andrew Clayton, T., Lindon, John C., Cloarec, Olivier, Antti, Henrik, Charuel, Claude, Hanton, Gilles, Provost, Jean-Pierre, Le Net, Jean-Loïc, Baker, David, Walley, Rosalind J., Everett, Jeremy R., Nicholson, Jeremy K.·2006·Nature

DOI 10.1038/nature04648

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Abstract

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 be enabled 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.

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Authors: Andrew Clayton, T., Lindon, J. C., Cloarec, O., Antti, H., Charuel, C., Hanton, G., Provost, J.-P., Le Net, J.-L., Baker, D., Walley, R. J., Everett, J. R., & Nicholson, J. K.
Affiliations: Imperial College London (GB)
Umeå University (SE)
Pfizer (France) (FR)
Pfizer (United States) (US)
Pfizer (United Kingdom) (GB)
ORCID: Lindon, John C.
Cloarec, Olivier
Antti, Henrik
Walley, Rosalind J.
Everett, Jeremy R.
Nicholson, Jeremy K.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2006-04-01
Volume: 440
Issue: 7087
Pages: 1073-1077
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature04648
OpenAlex: W1968593126
Cited by: 824
References: 32
Citations by year: 2026: 10 · 2025: 21 · 2024: 17 · 2023: 31 · 2022: 27 · 2021: 29 · 2020: 29 · 2019: 32 · 2018: 39 · 2017: 39 · 2016: 50 · 2015: 62 · 2014: 57 · 2013: 47 · 2012: 62
FWCI: 53.17
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Greenwich Academic Literature Archive (University of Greenwich) (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: Pfizer
Wellcome Trust
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Keywords: drug response prediction, urinary metabolites, paracetamol, liver injury, interindividual variability, gut microbiota, chemometrics
MeSH terms: Acetaminophen, Animals, Environment, Individuality, Liver, Male, Models, Biological, Magnetic Resonance Spectroscopy, Pharmacogenetics, Phenotype, Rats, Sprague-Dawley, Rats

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Pharmaco-metabonomic phenotyping and personalized drug treatment

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