title: Pharmaco-metabonomic phenotyping and personalized drug treatment.
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.
authors.affiliation: Biological Chemistry, Biomedical Sciences Division, Faculty of Natural Sciences, Sir Alexander Fleming Building, Imperial College London, South Kensington, London SW7 2AZ, UK.
authors.forename: T Andrew
authors.initials: TA
authors.lastname: Clayton
authors.forename: John C
authors.initials: JC
authors.lastname: Lindon
authors.forename: Olivier
authors.initials: O
authors.lastname: Cloarec
authors.forename: Henrik
authors.initials: H
authors.lastname: Antti
authors.forename: Claude
authors.initials: C
authors.lastname: Charuel
authors.forename: Gilles
authors.initials: G
authors.lastname: Hanton
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Provost
authors.forename: Jean-Loïc
authors.initials: JL
authors.lastname: Le Net
authors.forename: David
authors.initials: D
authors.lastname: Baker
authors.forename: Rosalind J
authors.initials: RJ
authors.lastname: Walley
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Everett
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Nicholson
mesh_terms: D000082:Acetaminophen / Q000378:metabolism / Q000494:pharmacology* / Q000652:urine; D000818:Animals; D004777:Environment; D007206:Individuality; D008099:Liver / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008954:Models, Biological; D010597:Pharmacogenetics; D010641:Phenotype; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000082:Acetaminophen