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| Pharmaco-metabonomic phenotyping and personalized drug treatment |
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| Author(s): Clayton TA, Lindon JC, Cloarec O, Antti H, Charuel C, Hanton G, Provost JP, Le Net JL, Baker D, Walley RJ, Everett JR, Nicholson JK |
| Source: NATURE Volume: 440 Issue: 7087 Pages: 1073-1077 Published: APR 20 2006 |
| Times Cited: 141 References: 30 |
| 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(1,2). 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(3-5). 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(6,7). 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. |
| Document Type: Article |
| Language: English |
| Reprint Address: Nicholson, JK (reprint author), Univ London Imperial Coll Sci Technol & Med, Fac Nat Sci, Div Biomed Sci, Sir Alexander Fleming Bldg, London SW7 2AZ, England |
Addresses:
1. Univ London Imperial Coll Sci Technol & Med, Fac Nat Sci, Div Biomed Sci, London SW7 2AZ, England
2. Umea Univ, Dept Chem, S-90187 Umea, Sweden
3. Pfizer Global Res & Dev, Ctr Rech, F-37401 Amboise, France
4. Pfizer Inc, Ann Arbor, MI 48105 USA
5. Pfizer Ltd, Global Res & Dev, Sandwich CT13 9NJ, Kent England |
| Publisher: NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND |
| Subject Category: Multidisciplinary Sciences |
| IDS Number: 034DL |
| ISSN: 0028-0836 |
| DOI: 10.1038/nature04648 |
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