Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Pharmaco-metabonomic phenotyping and personalized drug treatment


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type



Prices may be subject to local taxes which are calculated during checkout

Figure 1: Preliminary studies and the pharmaco-metabonomic hypothesis.
Figure 2: Representative1H NMR spectra.
Figure 3: Pre-dose prediction of the urinary mole ratio of paracetamol glucuronide to paracetamol (G/P) obtained in paracetamol-dosed rats.
Figure 4: Pre-dose discrimination of the degree of liver damage obtained in paracetamol-dosed rats.


  1. Spear, B. B., Heath-Chiozzi, M. & Huff, J. Clinical application of pharmacogenetics. Trends Mol. Med. 7, 201–204 (2001)

    Article  CAS  Google Scholar 

  2. Pagliarulo, V., Datar, R. H. & Cole, R. J. Role of genetic and expression profiling in pharmacogenomics: the changing face of patient management. Curr. Issues Mol. Biol. 4, 101–110 (2002)

    CAS  PubMed  Google Scholar 

  3. Ingelman-Sundberg, M. Genetic variability in susceptibility and response to toxicants. Toxicol. Lett. 120, 259–268 (2001)

    Article  CAS  Google Scholar 

  4. Nebert, D. W., Jorge-Nebert, L. & Vesell, E. S. Pharmacogenomics and “individualized drug therapy”: high expectations and disappointing achievements. Am. J. Pharmacogenomics 3, 361–370 (2003)

    Article  Google Scholar 

  5. van Aken, J., Schmedders, M., Feuerstein, G. & Kollek, R. Prospects and limits of pharmacogenetics: the thiopurine methyl transferase (TPMT) experience. Am. J. Pharmacogenomics 3, 149–155 (2003)

    Article  CAS  Google Scholar 

  6. Rang, H. P., Dale, M. M. & Ritter, J. M. Pharmacology (Churchill Livingstone, Edinburgh, 1995)

    Google Scholar 

  7. Tannock, G. W. Normal Microflora: An Introduction to Microbes Inhabiting the Human Body (Chapman and Hall, London, 1995)

    Google Scholar 

  8. Nicholson, J. K., Lindon, J. C. & Holmes, E. ‘Metabonomics’: understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR data. Xenobiotica 29, 1181–1189 (1999)

    Article  CAS  Google Scholar 

  9. Lindon, J. C., Nicholson, J. K., Holmes, E. & Everett, J. R. Metabonomics: metabolic processes studied by NMR spectroscopy of biofluids combined with pattern recognition. Concepts Magn. Reson. 12, 289–320 (2000)

    Article  CAS  Google Scholar 

  10. Nicholson, J. K., Connelly, J., Lindon, J. C. & Holmes, E. Metabonomics: a platform for studying drug toxicity and gene function. Nature Rev. Drug Discov. 1, 153–161 (2002)

    Article  CAS  Google Scholar 

  11. Nicholson, J. K. & Wilson, I. D. Understanding ‘global’ systems biology: metabonomics and the continuum of metabolism. Nature Rev. Drug Discov. 2, 668–676 (2003)

    Article  CAS  Google Scholar 

  12. Lindon, J. C. et al. The Consortium for Metabonomic Toxicology (COMET): aims, activities and achievements. Pharmacogenomics 6, 691–699 (2005)

    Article  CAS  Google Scholar 

  13. Shockcor, J. P. & Holmes, E. Metabonomic applications in toxicity screening and disease diagnosis. Curr. Top. Med. Chem. 2, 35–51 (2002)

    Article  CAS  Google Scholar 

  14. Rawson, E. S., Clarkson, P. M., Price, T. B. & Miles, M. P. Differential response of muscle phosphocreatine to creatine supplementation in young and old subjects. Acta Physiol. Scand. 174, 57–65 (2002)

    Article  CAS  Google Scholar 

  15. Zuppi, C. et al. 1H NMR spectra of normal urines: reference ranges of the major metabolites. Clin. Chim. Acta 265, 85–97 (1997)

    Article  CAS  Google Scholar 

  16. Zoratti, R. A review on ethnic differences in plasma triglycerides and high-density-lipoprotein cholesterol: is the lipid pattern the key factor for the low coronary heart disease rate in people of African origin? Eur. J. Epidemiol. 14, 9–21 (1998)

    Article  CAS  Google Scholar 

  17. Lenz, E. M. et al. Metabonomics, dietary influences and cultural differences: a 1H NMR-based study of urine samples obtained from healthy British and Swedish subjects. J. Pharm. Biomed. Anal. 36, 841–849 (2004)

    Article  CAS  Google Scholar 

  18. Waterfield, C. J., Turton, J. A., Scales, M. D. C. & Timbrell, J. A. The correlation between urinary and liver taurine levels and between pre-dose urinary taurine and liver damage. Toxicology 77, 1–5 (1993)

    Article  CAS  Google Scholar 

  19. Waters, E. et al. Role of taurine in preventing acetaminophen-induced hepatic injury in the rat. Am. J. Physiol. Gastrointest. Liver Physiol. 280, G1274–G1279 (2001)

    Article  CAS  Google Scholar 

  20. Timbrell, J. A., Seabra, V. & Waterfield, C. J. The in vivo and in vitro protective properties of taurine. Gen. Pharmacol. 26, 453–462 (1995)

    Article  CAS  Google Scholar 

  21. Coomes, M. W. in Textbook of Biochemistry with Clinical Correlations (ed. Devlin, T. M.) 473–474 (Wiley-Liss, New York, 1997)

    Google Scholar 

  22. Liu, L. & Klaassen, C. D. Different mechanisms of saturation of acetaminophen sulfate conjugation in mice and rats. Toxicol. Appl. Pharmacol 139, 128–134 (1996)

    Article  CAS  Google Scholar 

  23. Smith, J. L., Wishnok, J. S. & Deen, W. M. Metabolism and excretion of methylamines in rats. Toxicol. Appl. Pharmacol. 125, 296–308 (1994)

    Article  CAS  Google Scholar 

  24. Nicholls, A. W., Mortishire-Smith, R. J. & Nicholson, J. K. NMR spectroscopic-based metabonomic studies of urinary metabolite variation in acclimatizing germ-free rats. Chem. Res. Toxicol. 16, 1395–1404 (2003)

    Article  CAS  Google Scholar 

  25. Grant, D. M., Tang, B. K. & Kalow, W. A simple test for acetylator phenotype using caffeine. Br. J. Clin. Pharmacol. 58, S788–S793 (2004)

    Article  CAS  Google Scholar 

  26. Cloarec, O. et al. Evaluation of the O-PLS limitations caused by chemical shift variability and improved visualization of biomarker changes in 1H NMR spectroscopic metabonomic studies. Anal. Chem. 77, 517–526 (2005)

    Article  CAS  Google Scholar 

  27. Cloarec, O. et al. Statistical total correlation spectroscopy: an exploratory approach for latent biomarker identification from metabolic 1H NMR data sets. Anal. Chem. 77, 1282–1289 (2005)

    Article  CAS  Google Scholar 

  28. Claridge, T. D. W. (ed.) High-Resolution NMR Techniques in Organic Chemistry. Tetrahedron Organic Chemistry Series 19 (Elsevier, Amsterdam, 1999)

  29. Bales, J. R., Sadler, P. J., Nicholson, J. K. & Timbrell, J. A. Urinary excretion of acetaminophen and its metabolites as studied by proton NMR spectroscopy. Clin. Chem. 30, 1631–1636 (1984)

    Article  CAS  Google Scholar 

  30. Gregus, Z., Madhu, C. & Klaassen, C. D. Species variation in toxication and detoxication of acetaminophen in vivo: a comparative study of biliary and urinary excretion of acetaminophen metabolites. J. Pharmacol. Exp. Ther. 244, 91–99 (1988)

    CAS  PubMed  Google Scholar 

Download references


We thank the technical staff of Pfizer Global R&D in Amboise, France, for their assistance in performing the animal-related work, and thank R. L. Smith for discussions. T.A.C. thanks Pfizer for financial support. O.C. acknowledges the support of the Wellcome Trust (BAIR project).

Author information

Authors and Affiliations


Corresponding author

Correspondence to Jeremy K. Nicholson.

Ethics declarations

Competing interests

Authors J.R.E., R.J.W., D.B., C.C., G.H. and J.-L.L.N. are employees of Pfizer. Authors J.K.N. and J.C.L. have interests in Metabometrix in addition to holding academic posts at Imperial College London. Authors T.A.C. and O.C. are employees of Imperial College London with T.A.C. funded by Pfizer. H.A. holds an academic post at the University of Umeå, Sweden. In addition, T.A.C., J.R.E., J.C.L. and J.K.N. are named as inventors on patent applications relating to pharmaco-metabonomic technologies.

Supplementary information

Supplementary Table 1

This table describes the system for scoring the histology in individual liver lobes in the paracetamol study. (DOC 26 kb)

Supplementary Figure 1

This figure relates to the system for scoring the histopathological changes observed in individual liver lobes in the paracetamol study and contains four photographs showing microscopically-visible liver changes typical of histology scores 0, 1, 2 and 3, respectively. (DOC 738 kb)

Supplementary Table 2

This table summarizes the results of the standard clinical chemistry analysis of the blood plasma samples taken at ca. 24 h post-dosing in the paracetamol study. (DOC 39 kb)

Supplementary Methods

This file contains a detailed description of the methodology employed in the paracetamol study and outline descriptions of the studies on galactosamine and allyl alcohol. (DOC 60 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Andrew Clayton, T., Lindon, J., Cloarec, O. et al. Pharmaco-metabonomic phenotyping and personalized drug treatment. Nature 440, 1073–1077 (2006).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing