The researchers used the new science of metabonomics to look at global human metabolism, and how it might interact with certain drugs, the environment and the gut microflora.
Professor Jeremy Nicholson from Imperial College London, comments: "The theory that the human metabolism may operate like a pinball machine is particularly fascinating and could explain a lot about drug toxicity and disease. We previously thought that metabolism operated in a more highly regulated manner, but we now know that a whole series of complex interactions take place which can result in both drug and endogenous molecules bouncing down various pathways like the balls in a Pachinko pinball machine."
This new model, advanced in today's Nature Drug Discovery could explain the basis of certain types of drug toxicity and even the way in which some important diseases develop. They suggest that human metabolism operates in a much more complex way than previously thought with our own genome, environmental factors and gut microbes also playing a significant role. All of these factors may contribute to the safety and efficacy profile of a compound.
Such factors may play a part in the development and progression of disease and in the complex area of how drugs interact with the body, by creating many more possible effects for drugs on the body. This can cost pharmaceutical companies many millions of dollars when drugs have to be withdrawn and can also adversely affect patient quality of life.
The researchers used the way Japanese Pachinko machines operate as a model to explain the interactions of our genes with drugs, the environment and microbial metabolism. Their theory states that metabolic interactions are often highly probabilistic and the flows of molecules through the machine are dependent on combinations of genetic variations with factors such as diet and the composition of the gut microflora.
Dr Ian Wilson from AstraZeneca Research and Development, adds: "The composition of the gut microflora, the community of microbes in the intestine, are very poorly understood, but they are crucially important to our health. There are about 100 trillion microbes in the average person, which is around ten times the number of cells in their body.
"This means it is not surprising that they might have big effects, and we believe that the exact species composition might determine the way in which some drugs are metabolised, affecting their efficacy. "
Professor Nicholson adds: "There is a strong case for drug companies to start researching probiotics, which may affect microfloral composition. This concept opens up some new horizons in understanding the way disease processes work. It is no longer enough to consider disease just in relation to our own genes. Humans are part of an ecological system that includes our commensal and symbiotic microflora".
The researchers suggest that the recently developed science of metabonomics may be the best way to look at the mechanistic connectivities between genetic constitution, gut microbes and disease.
Metabonomics is a holistic approach for examining the dynamic metabolic changes in whole organisms. It can be used to provide information on drug toxicity and efficacy, clinical diagnostics and gene function. The technology was originally developed in order to help the development of safer of drugs but has many clinical applications as well.
Notes to editors:
1. Understanding Global Systems Biology: Metabonomics and the Continuum of Metabolism, Nature Drug Discovery, 1 August 2003, P668-676.
2. Consistently rated in the top three UK university institutions, Imperial College London is a world leading science-based university whose reputation for excellence in teaching and research attracts students (10,000) and staff (5,000) of the highest international quality. Innovative research at the College explores the interface between science, medicine, engineering and management and delivers practical solutions that enhance the quality of life and the environment - underpinned by a dynamic enterprise culture. Website: http://www.imperial.ac.uk
3. AstraZeneca is a major international healthcare business engaged in the research, development, manufacture and marketing of prescription pharmaceuticals and the supply of healthcare services. It is one of the top five pharmaceutical companies in the world with healthcare sales of over $17.8 billion and leading positions in sales of gastrointestinal, oncology, cardiovascular, neuroscience and respiratory products. AstraZeneca is listed in the Dow Jones Sustainability Index (Global and European) as well as the FTSE4Good Index.
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Journal
Nature Reviews Drug Discovery