Preclinical Development – Chemical
2019 PharmSci 360
Oral medicinal drugs can exhibit incomplete absorption in the upper gastrointestinal (GI) tract or reach the gut after enterohepatic circulation. In these circumstances, drugs encounter enormous densities of commensal microbes. These microbes collectively encode 150-fold more genes than the human genome, including a rich repository of enzymes with the potential to metabolize drugs. However, the contribution of the microbiome to drug and drug metabolite exposure in the GI tract and in circulation is largely unexplored.
I will describe examples that suggest that gut microbial activity can be responsible for a significant portion of systemic exposure to a toxic drug metabolite, even if the drug exhibits >80% bioavailability, the same metabolite is readily produced by hepatic extracts in vitro, and drug metabolite levels are low in feces. I will also discuss the first systematic exploration of microbiome-encoded drug metabolizing activity and how these studies can identify microbial genes that predict the capacity of an individual’s gut microbiome to metabolize a drug.