Drugging the Gut Microflora To Reduce Drug Toxicity

Drugging the Gut Microflora – DMPK Studies on Bacterial β-glucuronidase Inhibitors Drugging the Gut Microflora To Reduce Drug Toxicity Many drugs and their metabolites are excreted in the bile as glucuronide conjugates which are then deconjugated by gut bacteria to salvage the energy contained in the glucuronic acid. Whilst advantageous to the bacteria the effects may release aglycones that are toxic to the gut. Specifically inhibiting the bacterial Beta-glucuronidase therefore has the potential to reduce dose limiting gut toxicity and improve patient outcomes. However, as the target is specifically the gut, systemic exposure is arguably neither an issue nor indeed desirable. Here we describe in vitro and in vivo studies on two structurally dissimilar gut bacterial β-glucuronidase (GUS) inhibitors, UNC 10201652 ((4-(8-(piperazin-1-yl)-1,2,3,4-tetrahydro-[1,2,3]triazino [4',5':4,5]thieno[2,3- c]isoquinolin-5-yl)morpholine)) and Inh 1 ((1-((6,8-dimethyl-2-oxo-1,2-dihydroquinolin-3- yl)methyl)-3-(4-ethoxyphenyl)-1-(2-hydroxy-ethyl)thiourea)). UNC 10201652 showed extensive metabolism to a large number of metabolites in in vitro in human, mouse and rat microsomes and hepatocytes, with an absolute oral bioavailability of ca. 15% in mice for a 3 mg/kg dose (rising to ca. 180% with ABT pretreatment). Inh 1 showed similar extensive metabolism including a relatively novel desulfurization reaction. Following IV administration to mice (3 mg/kg) Inh 1 was found to have an absolute oral bioavailability of ca. 26 % Gut bacteria can influence how drugs are metabolized, potentially releasing toxic compounds into the gut. This webinar will explore the role of gut bacterial β-glucuronidase (GUS) in drug metabolism. Our expert speaker will dive into how inhibiting GUS enzymes can reduce gut toxicity, improving patient outcomes and allowing for higher, more effective doses. She’ll outline how in vitro and in vivo studies on two GUS inhibitors demonstrated their ability to prevent gut damage while undergoing metabolism in human, mouse and rat microsomes, opening avenues for the development of gut-targeted GUS inhibitors with unique metabolic pathways. • Understand the impact of GUS on drug metabolism and toxicity. • Explore the role of GUS inhibitors in reducing drug-induced gut damage, particularly with irinotecan. • Learn about the in vitro and in vivo metabolism of two GUS inhibitors. • Recognize the importance of species differences in drug metabolism and their implications for drug development. Anna Kerins Principal Scientist Cyprotex