The gut microbiome refers to all the microbes present in your intestines. It’s incredible to think that there are approximately 40 trillion microbes in your body and up to 1000 species of bacteria in the human gut microbiome. Each bacteria plays a different role within the body. Some cause disease but most are important for your health. As well as digestion they have been shown to play a role in controlling your immune system and brain health as well as other bodily processes. In fact, an imbalance of unhealthy to heathy microbes in the intestines is thought to contribute to weight gain, high blood sugar, high cholesterol and other disorders. For this reason, it has become an area of considerable scientific interest.
The gut microbiome has been shown to contribute towards drug metabolism as it contains a range of metabolic enzymes predominantly involved in reduction and hydrolysis. One class of gut microbial enzymes which is of particular interest is the bacterial β-glucuronidase (GUS) which has the ability to reverse Phase II glucuronidation and may therefore result in the GI toxicity of several drugs. For example, irinotecan is metabolized to an active and toxic metabolite, SN-38, which is then inactivated into non-toxic SN-38 glucuronide by the liver. On transport back to the intestines via biliary excretion, the SN-38 glucuronide is broken back down to the toxic form (SN-38) by bacterial GUS enzymes, causing dose limiting diarrhoea. The bacteria subsequently use the glucuronic acid as an energy source. Selective inhibitors of the glucuronidases (for example, UNC10201652 and Inhibitor 1) have been shown to reduce these side effects in rodents and allow a higher dose of irinotecan to be administered.
Our research at Cyprotex, in collaboration with Professors Ian Wilson and Matthew Redinbo, has explored the clearance and metabolic fate, the permeability and the plasma protein binding of the GUS inhibitors, UNC10201652 and Inhibitor 1, using a range of in vitro models. Extensive metabolism was observed for both inhibitors and species differences were observed in the metabolites formed. Both inhibitors exhibited high permeability in the Caco-2 assay. The data suggest some active efflux. Plasma protein binding was >90% in all species for Inhibitor 1 and UNC10201652 with the exception of the rat for UNC10201652 which was 89% bound.
This research was presented at a recent webinar by Cyprotex Principal Scientist, Anna Kerins. The webinar is now available for you to watch on demand.
