There are several reasons why some patients may or may not respond to a drug, or may exhibit a certain side effect that other patients do not. Some of those reasons are genetic, as pharmacogenomics researchers have shown certain alleles can predict response to a drug or the likelihood of an adverse reaction. But pharmacogenomics has been unable to explain all the variability in drug response, so metabolomics researchers have stepped in to see whether their discipline can help explain why some patients respond to drugs the way they do.
While metabolomics researchers look at metabolic profiles in plasma, serum, or urine to determine the differences between people with a certain disease and healthy people, pharmacometabolomics- is an extension of that, says Imperial College London's John Lindon. "Once you've got the biomarkers of the disease these are the metabolites you can go back and look for the mechanism by looking at the enzyme pathways, to see which pathways are involved in using up those metabolites," Lindon says. "We look at a group of people's urine and we look for metabolic differences in the pre-dose, which would then be predictive of what happened post-dose."
Like pharmacogenomic researchers, pharmacometabolomic researchers look for signals in a person's biology that may indicate why a drug affects a person the way it does. But instead of looking at genetic differences, these researchers look at differences in enzymes, metabolites, and small molecules. Using nuclear magnetic resonance spectroscopy and different kinds of mass spectrometry, "we look for the metabolic fingerprint that says this person would process this drug differently it might be more toxic in that person or more beneficial in that person. The idea would be to go towards personalized medicine," Lindon adds. His group published the first pharmacometabo-lomic study on pharmacometabolomic phenotyping and its potential use as a personalized medicine tool, in Nature in April 2006.
The benefit of looking at drug response on a metabolic level rather than a genomic level, Lindon says, is that while genomics reveals everything about a person's DNA, it says nothing at all about a person's environment. "Epigenetics tells you about your environment, but genetics and genomics people are largely blind to the environmental influences," he adds. "Metabolism is the endpoint of all the processes of the body, and is exquisitely sensitive to environment."
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