Microbial contribution to drug metabolism. Microbial contribution to drug metabolism. Following enteral administration, the physiochemical properties or formulation of a drug impacts the region of the gastrointestinal tract where the major exposure to microbial drug metabolism occurs. The nature of these interactions depends on whether the compounds encountered by the gut microbiome are poorly absorbed or are first conjugated by the liver and subsequently reach the intestine via biliary excretion, which is also a route through which i.v. administered drugs can become subject to chemical transformation by gut microbes. The majority of orally administered drugs are normally absorbed in the upper small intestine assuming that the drug is highly soluble and highly permeable in this region. Although there is a lower density of microbes in the small intestine, we have an incomplete understanding of the impact of microbial activity in different regions of the gastrointestinal tract, and there may be important implications of region-specific microbial drug metabolism for health and disease. However, many drugs display poor solubility, which can lead to slow and incomplete absorption with the drug being absorbed from distal regions of the small intestine and/or the colon. Drugs with low permeability through the intestinal membrane can lead to greater amounts of those drugs reaching these distal regions of the intestine. Drugs can also become a candidate substrate for direct microbial processing if they are appropriately formulated. The highest density of bacteria is found in the colon, and the prevalent use of advanced drug formulations designed for extended release (e.g., sustained release tablets) is on the increase, circumventing absorption profiles that would usually limit exposure of many drugs to the colonic gut microbiota. This ensures that an increasing number of pharmaceuticals are first exposed to the gut microbiota and their associated collection of metabolic enzymes with the potential for relevant microbiome–drug interactions highest in this region. The fate of drugs following oral ingestion is most often considered, but parenteral routes can still lead to gut microbiome–drug interactions, for example, via the splanchnic circulation and bilary excretion. Enterohepatic circulation is an important consideration in this regard, as is the potential for an indirect impact via microbial regulation of hepatic drug metabolism. Gerard Clarke et al. Pharmacol Rev 2019;71:198-224 Copyright © 2019 The Author(s).