Urine samples could be used to predict responses to drugs, say researchers

Researchers show you can predict drug responses by looking at the products of metabolism in people's urine <em> - News Release</em>

Imperial College London and Pfizer News Release

Under STRICT EMBARGO for 15.00 US Eastern Time / 20.00 British Summer Time
Monday 10 August 2009

Researchers may be able to predict how people will respond to particular drugs by analysing their urine samples, suggest scientists behind a new study published today in the journal Proceedings of the National Academy of Sciences.

Not all drugs are effective in all patients and occasionally, susceptible individuals can have adverse reactions to them. In today's study, researchers from Imperial College London and Pfizer Research and Development showed that it was possible to predict how different individuals would deal with one drug by looking at the levels of different products of metabolism, known as metabolites, in their urine before they took a dose of the drug.

The researchers say that this kind of 'metabolic profiling' could ultimately be a valuable tool for predicting how different individuals will react to drugs, enabling those developing drugs to match drug treatments to individuals' requirements and avoid adverse side effects. They argue that those developing new, personalised approaches to medicine will need to consider metabolic as well as genetic profiling when developing drugs, in order to produce a complete picture of different individuals' makeup.

Metabolic profiles reflect complex gene-environment interactions and the activities of gut bacteria – factors that can influence drug metabolism and toxicity.

Bacteria in the gut, or gut microbes, live symbiotically in human and animal bodies and there is growing recognition that they play an important part in influencing people’s metabolic makeup. Today's study provides evidence that gut microbes can have a crucial role in determining a person's response to a particular drug.

The new study looked at 99 healthy male volunteers aged between 18 and 64, taking one dose of the commonly used painkiller acetaminophen, widely known as paracetamol in the UK. The researchers took urine samples from the men before they took the paracetamol dose and for six hours afterwards and analysed the metabolites in the samples using 1H NMR spectroscopy.

The results revealed that a compound called para-cresol sulphate, which is derived from para-cresol produced by bacteria in the gut, was an indicator of how the men would metabolise the dose of paracetamol. Those with higher levels of para-cresol sulphate metabolised the drug in a different way from those with lower levels. The scientists suggest that this is because the body uses compounds containing sulphur to process drugs like paracetamol effectively and para-cresol can deplete sulphur compounds in the body.

Researchers analysed urine samples from the volunteers before they took a paracetamol dose and for six hours afterwards

The body uses sulphur to process a variety of drugs, not just paracetamol, so the new findings about para-cresol could have significant implications for a whole group of drugs, say the researchers. Further work is now needed to explore areas such as the relationship between para-cresol and other drugs, and whether para-cresol has any relevance to instances of accidental paracetamol poisoning.

The researchers also suggest that where the bacteria in the gut are affecting the body's ability to process a particular drug, it might ultimately be possible to alter the makeup of these bacteria so that the body can process a variety of drugs more effectively and safely.

Professor Jeremy Nicholson, senior author of the study from the Department of Biomolecular Medicine at Imperial College London, said: "This result is very encouraging. Pre-clinical studies had suggested it might be possible to predict how individuals would react to drugs by looking at their pre-dose metabolite profiles, but this is the first time that anyone has been able to show convincingly that such a test could work in humans. The beauty of pre-dose metabolite profiling is that it can tap into both genetic and environmental factors influencing drug treatment outcomes.

"Our finding also highlights the potential importance of the gut bacteria in determining how different people react to drug treatments. The study gave us some unexpected insights into the comparative ease with which the body’s sulphur-containing reserves can be depleted in normal adults by exposure to microbial metabolites. This may have more widespread implications relating to understanding the development of a number of diseases where disruption of sulphur metabolism is an important factor," added Professor Nicholson.

Dr Jeremy Everett, the Vice President of the Research Centres of Emphasis in Pfizer Global Research and Development at Sandwich, UK, and another author of the study, said: "Pfizer and other drug companies are using genetic information both to select the targets that drugs act against, and also to select the patients who will benefit most from treatment with a particular drug in clinical trials and when a drug is on the market. Although this is the first study of its kind and much further research is needed, this finding shows that in the future, researchers may need to consider human metabolic profiles as well as genetic profiles when choosing targets for drug discovery programs and when selecting patients for future clinical trials."

-ends-

For further information please contact:

Laura Gallagher
Research Media Relations Manager
Imperial College London
e-mail: l.gallagher@imperial.ac.uk
Telephone: +44 (0)207 594 8432 or ext. 48432
Out of hours duty Press Officer: +44 (0)7803 886 248

Monica Pinuela
Pfizer
Email: Monica.pinuela@pfizer.com
Tel: +34 647 37 62 85

Notes to editors:

1. "Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism"

Proceedings of the National Academy of Sciences, 10 August 2009

Corresponding author: Professor Jeremy Nicholson, Imperial College London (for full list of authors please see pape r)

2. About Imperial College London

Consistently rated amongst the world's best universities, Imperial College London is a science-based institution with a reputation for excellence in teaching and research that attracts 13,000 students and 6,000 staff of the highest international quality. Innovative research at the College explores the interface between science, medicine, engineering and business, delivering practical solutions that improve quality of life and the environment - underpinned by a dynamic enterprise culture.

Since its foundation in 1907, Imperial's contributions to society have included the discovery of penicillin, the development of holography and the foundations of fibre optics. This commitment to the application of research for the benefit of all continues today, with current focuses including interdisciplinary collaborations to improve health in the UK and globally, tackle climate change and develop clean and sustainable sources of energy.

Website: www.imperial.ac.uk

3. Pfizer Inc: Working together for a healthier world™

Founded in 1849, Pfizer is the world's premier biopharmaceutical company taking new approaches to better health. We discover, develop, manufacture and deliver quality, safe and effective prescription medicines to treat and help prevent disease for both people and animals. We also partner with healthcare providers, governments and local communities around the world to expand access to our medicines and to provide better quality health care and health system support. At Pfizer, more than 80,000 colleagues in more than 90 countries work every day to help people stay happier and healthier longer and to reduce the human and economic burden of disease worldwide.