Pharmaco-metabonomic phenotyping and personalized drug treatment
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- 1 April 2006
- journal article
- letter
- Published by Springer Nature in Nature
- Vol. 440 (7087) , 1073-1077
- https://doi.org/10.1038/nature04648
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 reactions1,2. 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 excretion3,4,5. 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 drugs6,7. 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.Keywords
This publication has 25 references indexed in Scilit:
- Evaluation of the Orthogonal Projection on Latent Structure Model Limitations Caused by Chemical Shift Variability and Improved Visualization of Biomarker Changes in 1H NMR Spectroscopic Metabonomic StudiesAnalytical Chemistry, 2004
- A simple test for acetylator phenotype using caffeineBritish Journal of Clinical Pharmacology, 2004
- Metabonomics, dietary influences and cultural differences: a 1H NMR-based study of urine samples obtained from healthy British and Swedish subjectsJournal of Pharmaceutical and Biomedical Analysis, 2004
- Metabonomics: a platform for studying drug toxicity and gene functionNature Reviews Drug Discovery, 2002
- Differential response of muscle phosphocreatine to creatine supplementation in young and old subjectsActa Physiologica Scandinavica, 2002
- 'Metabonomics': understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic dataXenobiotica, 1999
- Different Mechanism of Saturation of Acetaminophen Sulfate Conjugation in Mice and RatsToxicology and Applied Pharmacology, 1996
- The in vivo and in vitro protective properties of taurineGeneral Pharmacology: The Vascular System, 1995
- Metabolism and Excretion of Methylamines in RatsToxicology and Applied Pharmacology, 1994
- The correlation between urinary and liver taurine levels and between pre-dose urinary taurine and liver damageToxicology, 1993