The human metabolism is often able to chemically modify small molecules designed to treat a specific disease. While some drugs are simply inactivated by this process, other metabolic byproducts can be harmful, complicating the safety profile analysis of a new drug. However, a more daunting problem in evaluating the efficacy and safety of drugs is the analysis of the collective metabolic pathways of the gut microbiota and what impact it could have on drugs.
An example for this problem is the chemotherapeutic agent irinotecan, and its active metabolite SN-38, which was discussed during Merck & Co’s Human Microbiome Symposium held in Boston on May 9. Irinotecan is a commonly used drug to treat various forms of cancer ranging from colorectal to pancreatic and small-lung cancer. While the human metabolism modifies SN-38 to a harmless compound (SN-38-G) via a glucuronosyltransferase, SN-38-G can then be converted back to the active SN-38 by beta-glucuronidases (GUS) produced by the gut microbiota. In the gut, this results in gastrointestinal toxicity, and many patients consequently suffer from severe diarrhea (Grade 3-4) due to this conversion, often requiring a dose reduction of administered irinotecan, reducing the drug’s efficacy during cancer treatment.
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The research group around Prof. Redinbo from the University of North Carolina at Chapel Hill identified a possible inhibitor of bacterial GUS and when administered to mice, the inhibitor prevented mice from developing bloody diarrhea in combination with irinotecan.
Furthermore, the researchers also demonstrated a direct impact of the inhibitor on the gut microbiome. While Enterobacteriaceae typically compose only about 4% of a healthy human gut microbiome, patients suffering from diarrhea due to irinotecan administration might have over 40% Enterobacteriaceae, representing a harmful density of these bacteria. Testing the inhibitor in a mice model, irinotecan in combination with the inhibitor had a less severe impact on the gut microbiome while the inhibitor alone, in the absence of irinotecan, even resulted in a reduction of Enterobacteriaceae to 0.4%. In addition, some preliminary data indicated that the inhibitor might allow increased doses of irinotecan to be administered, possibly even enhancing the overall efficacy of this cancer treatment.
Similarly to irinotecan, the gut microbiome can also be responsible for the possible toxicity of nonsteroidal anti-inflammatory drugs (NSAIDs), and Prof. Redinbo alluded to the identification of a potent, selective, and non-toxic inhibitor able to reduce the metabolic activity in the gut microbiome responsible for this toxicity.
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Collectively, these data show that the metabolic pathways utilized by the gut microbiome harbor many potential threats for drug efficacy and safety while also providing unique market opportunities to tailor pharmaceutical products directly targeting specific gut bacteria or enhancing the efficacy of already marketed drug. Hence, our advancing knowledge of the gut microbiome opens up new avenues for the pharmaceutical industry to combat human diseases.
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University of North Carolina