In vitro metabolism of targeted covalent inhibitors and their thiol conjugates by gut microbiome from rats, mice, and humans.

Targeted covalent inhibitor (TCI) represents a noncanonical class of small molecules that function via "inactivating" the target protein through the formation of drug-protein adducts. The electrophilic groups (warheads) embedded in the TCIs are essential for their activity while also being recognized as sites susceptible to metabolism by various enzymes and endogenous nucleophiles. Given the growing knowledge of gut microbiome-mediated drug metabolism and its impact on drug absorption, distribution, metabolism, and excretion, the fate of the reactive warhead-containing TCIs in the gut warrants further understanding.

Dissecting the human gut microbiome to better decipher drug liability: A once-forgotten organ takes center stage.

Background: The gut microbiome is a diverse system within the gastrointestinal tract composed of trillions of microorganisms (gut microbiota), along with their genomes. Accumulated evidence has revealed the significance of the gut microbiome in human health and disease. Due to its ability to alter drug/xenobiotic pharmacokinetics and therapeutic outcomes, this once-forgotten "metabolic organ" is receiving increasing attention.