Journal Article

Pharmaco-metabonomic phenotyping and personalized drug treatment

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

2006

Overview

Medicines for one We may one day benefit from 'personalized medicine', which will involve analysing key characteristics of an individual and predicting which drugs will be effective for that patient. Although the pharmacogenomic approach looked promising, its usefulness is limited as it does not take account of potentially important environmental factors. Enter 'pharmaco-metabonomics', which uses a combination of pre-dose metabolite profiling and chemometrics to model and predict the response of an individual. A 'proof-of-principle' for this approach, in which the metabolic effects of paracetamol in rats were predicted, is published this week. This approach involves the analysis of a patient's metabolic phenotype, which is influenced not only by genotype but also by factors such as nutritional status, age and disease, so it could be an important step towards personalized human healthcare. An alternative and conceptually new ‘pharmaco-metabonomic’ approach to personalizing drug treatment uses a combination of pre-dose metabolite profiling and chemometrics to model and predict the responses of individual subjects. 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 , 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 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.

• Publisher: Nature Publishing Group UK,Nature Publishing,Nature Publishing Group
• Subject: Absorption / Acetaminophen / Acetaminophen - metabolism / Acetaminophen - pharmacology / Acetaminophen - urine / Acetaminophen/metabolism/pharmacology/urine / Analysis / Animals / Biological and medical sciences / Dosage and administration / Drug therapy / Environment / Environmental factors / Excretion / General pharmacology / Genetic diversity / Genomics / Genotype & phenotype / Humanities and Social Sciences / Individuality / letter / Liver - drug effects / Liver - metabolism / Liver - pathology / Liver/drug effects/metabolism/pathology / Magnetic Resonance Spectroscopy / Male / Medical sciences / Metabolism / Metabolites / Metabonomic analysis / Models, Biological / multidisciplinary / Nutritional status / Patient outcomes / Pharmacogenetics / Pharmacogenomics / Pharmacokinetics. Pharmacogenetics. Drug-receptor interactions / Pharmacology. Drug treatments / Phenotype / Phenotypes / Precision medicine / Rats / Rats, Sprague-Dawley / Science / Side effects