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Metabonomic Profiling Provides Drug Metabolism Clues

NEW YORK (GenomeWeb News) – British researchers reported this week that metabolic profiling of urine samples prior to drug treatment could help predict an individual's response to the drug.

"[E]ven for this most familiar drug, pharmacometabonomic analysis will yield significantly increased understanding of its metabolic behavior in humans," the researchers wrote. "These findings have considerable implications for personalized drug treatment in general and lead to new and testable hypotheses for a number of diseases."

Researchers from Imperial College London and Pfizer used 1H NMR spectroscopy to characterize metabolites in urine samples from almost 100 men between the ages of 18 and 64 years old before and up to six hours after they took the painkiller acetaminophen, also known as paracetamol. Using this "metabonomic" approach, they found that individuals whose urine had high levels of a compound called para-cresol sulfate before taking the drug appeared to metabolize acetaminophen slightly differently than others.

And because para-cresol sulfate is a derivative of the bacterial compound para-cresol, the research, which appears online in the Proceedings of the National Academy of Sciences, suggests that gut microbes contributing to human metabolism also influence drug response.

"The beauty of pre-dose metabolite profiling is that it can tap into both genetic and environmental factors influencing drug treatment outcomes," senior author Jeremy Nicholson, biological chemistry chair at the Imperial College London, said in a statement. "Our finding also highlights the potential importance of the gut bacteria in determining how different people react to drug treatments."

The researchers obtained urine samples from 99 healthy, non-smoking men between 18 and 64 years old, collected before taking acetaminophen and for up to six hours after a standard dose of the drug (two 500 milligram tablets). The participants had not taken any drugs the week before the study. The metabolic profiles in these samples were assessed by 1H NMR spectroscopy using a Bruker Avance 600 NMR spectrometer.

Among the potentially predictive metabolites was para-cresol sulfate, a compound excreted in higher pre-drug levels in some than others. Those with higher pre-drug para-cresol sulfate levels also tended to excrete less sulfonation-related acetominophen products in their urine after taking the drug.

Because O-sulfonation is one of the pathways by which the human body metabolizes acetominophen (along with glucuronidation), the researchers speculated that individuals carrying para-cresol producing gut bacteria might shift their acetaminophen metabolism away from sulfonation due to competition between para-cresol and acetaminophen compounds for enzyme active sites and sulfonate donor compounds.

"The study gave us some unexpected insights into the comparative ease with which the body's sulfur-containing reserves can be depleted in normal adults by exposure to microbial metabolites," Nicholson said.

Their subsequent experiments supported the researchers' hypothesis that "production of endogenous [para]-cresol can reduce an individual's ability to sulfonate acetaminophen by acting as a competitive substrate." They also predicted that, over time, exposure to para-cresol and acetaminophen might make individuals more prone to liver toxicity by decreasing the amount of O-sulfonation metabolized drug — though that theory is yet to be tested.

Based on this proof of principle study, the team argued that metabolic profiling warrants additional study and may become important for understanding drug response as well as some human diseases. In addition, they emphasized the importance of accounting for microbiome-related effects and suggested that it might be possible to manipulate this microbial community to improve drug efficacy and curb adverse drug reactions.

"Although this is the first study of its kind and much further research is needed," co-author Jeremy Everett, vice president of Pfizer Global Research and Development's Research Centres of Emphasis in the UK, said in a statement, "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."

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