From metabonomics to pharmacometabonomics: The role of metabolic profiling in personalized medicine

Variable patient responses to drugs are a key issue for medicine and for drug discovery and development. Personalised medicine, that is the selection of medicines for subgroups of patients so as to maximise drug efficacy and minimise toxicity, is a key goal of 21st century healthcare. Currently, most personalised medicine paradigms rely on clinical judgement based on the patient’s history, and on the analysis of the patients’ genome to predict drug effects i.e. pharmacogenomics. However, variability in patient responses to drugs is dependent upon many environmental factors to which human genomics is essentially blind. A new paradigm for predicting drug responses based on individual pre-dose metabolite profiles has emerged in the past decade: pharmacometabonomics, which is defined as ‘the prediction of the outcome (for example, efficacy or toxicity) of a drug or xenobiotic intervention in an individual based on a mathematical model of pre-intervention metabolite signatures’. The new pharmacometabonomics paradigm is complementary to pharmacogenomics but has the advantage of being sensitive to environmental as well as genomic factors. This review will chart the discovery and development of pharmacometabonomics, and provide examples of its current utility and possible future developments

NMR-based pharmacometabonomics: A new paradigm for personalised or precision medicine

Metabolic profiling by NMR spectroscopy or hyphenated mass spectrometry, known as metabonomics or metabolomics, is an important tool for systems-based approaches in biology and medicine. The experiments are typically done in a diagnostic fashion where changes in metabolite profiles are interpreted as a consequence of an intervention or event; be that a change in diet, the administration of a drug, physical exertion or the onset of a disease. By contrast, pharmacometabonomics takes a prognostic approach to metabolic profiling, in order to predict the effects of drug dosing before it occurs. Differences in pre-dose metabolite profiles between groups of subjects are used to predict post-dose differences in response to drug administration. Thus the paradigm is inverted and pharmacometabonomics is the metabolic equivalent of pharmacogenomics. Although the field is still in its infancy, it is expected that pharmacometabonomics, alongside pharmacogenomics, will assist with the delivery of personalised or precision medicine to patients, which is a critical goal of 21st century healthcare

Could urinary metabolomics help identifying biomarkers to optimize the use of anticancer drugs?

Le MTX est un agent anticancéreux utilisé à hautes doses pour le traitement des hémopathies malignes et de certaines tumeurs solides. Il présente une importante variabilité pharmacocinétique (PK) traduite par des surexpositions à l'origine de toxicités très sévères, surtout lors d'une administration à haute dose. Les retards d'élimination du MTX surviennent encore de manière inattendue et il n'existe à ce jour aucun biomarqueur qui permette un diagnostic précoce du risque de surexposition. Nos travaux ont focalisé sur les déterminants de l'élimination rénale du MTX, et en particulier le rôle du transporteur MRP2/ABCC2 dans ce processus. Ce travail s'inscrit donc (1) dans la recherche de biomarqueurs métabolomiques urinaires prédictifs de la PK du MTX et (2) dans l'identification de substrats endogènes de MRP2 parmi un panel de 217 acides organiques urinaires analysés par chromatographie gazeuse couplée à la spectrométrie de masse. Nos analyses ont abouti à un profil de 28 anions organiques endogènes, prédictifs de la CL MTX. L'outil était en revanche mal adapté à la prédiction des retards d'élimination. Pour la 2eme partie, nos résultats tendent à montrer que 8 métabolites urinaires sont des bio-marqueurs potentiels de l'activité de MRP2. Leur utilisation en clinique nécessite encore des études confirmatoires.MTX is an anticancer agent used at high doses for the treatment of malignant haemopathies and some solid tumors. It presents an important pharmacokinetic variability (PK), manifested by overexposures causing very severe toxicities, especially when administered at high doses. Delayed elimination of MTX still occurs unexpectedly and there is currently no biomarker that allows early diagnosis of the risk of overexposure. Our work focused on the determinants of renal elimination of MTX, and particularly on the role of MRP2 / ABCC2 in this process. This work is therefore devoted to (1) the search for metabolomic biomarkers predictive of MTX PK and (2) the identification of endogenous substrates of MRP2, from a panel of 217 urinary organic acids analyzed by gas chromatography-mass spectrometry. Our analyses resulted in a profile of 28 endogenous organic anions, predictive of CL MTX. The tool was, on the other hand, poorly adapted to the prediction of delayed elimination. For the second part, our results tend to show that 8 urinary metabolites are potential biomarkers of MRP2 activity. Their clinical use still requires confirmatory studies

Plasma pharmacokinetics of (poly)phenol metabolites and catabolites after ingestion of orange juice by endurance trained men

The health benefits of orange juice (OJ) consumption are attributed in part to the circulating flavanone phase II metabolites and their microbial-derived ring fission phenolic catabolites. The present study investigated these compounds in the bloodstream after acute intake of 500 mL of OJ. Plasma samples obtained at 0, 1, 2, 3, 4, 5, 6, 7, 8 and 24 h after OJ intake were analysed by HPLC-HR-MS. Eleven flavanone metabolites and 36 phenolic catabolites were identified and quantified in plasma. The main metabolites were hesperetin-3′-sulfate with a peak plasma concentration (Cmax) of 80 nmol/L, followed by hesperetin-7-glucuronide (Cmax 24 nmol/L), hesperetin-3′-glucuronide (Cmax 18 nmol/L) and naringenin-7-glucuronide (Cmax 21 nmol/L). Among the main phenolic catabolites to increase in plasma after OJ consumption were 3′-methoxycinnamic acid-4′-sulfate (Cmax 19 nmol/L), 3-hydroxy-3-(3′-hydroxy-4′-methoxyphenyl)propanoic acid (Cmax 20 nmol/L), 3-(3′-hydroxy-4′-methoxyphenyl)propanoic acid (Cmax 19 nmol/L), 3-(4′-hydroxyphenyl)propanoic acid (Cmax 25 nmol/L), and 3-(phenyl)propanoic acid (Cmax 19 nmol/L), as well as substantial amounts of phenylacetic and hippuric acids. The comprehensive plasma pharmacokinetic profiles that were obtained are of value to the design of future ex vivo cell studies, aimed at elucidating the mechanisms underlying the potential health benefits of OJ consumption