Property-Based Prediction Uncovers Intestinal Excretion as an Elimination Route of Small-Molecule Drugs

Hepatic and renal pathways are traditionally considered the primary routes of drug clearance. However, emerging evidence highlights the significant role of direct intestinal excretion of unchanged drugs and metabolites. Intestinal excretion is often unrecognized due to complications arising from unabsorbed drugs and direct biliary excretion. Consequently, the extent and mechanisms of intestinal excretion remain systematically underexplored. Using bile duct cannulated rats, we investigated intestinal excretion for a library of drugs and proposed a predicative decision tree based on molecular descriptors. Mechanistically, passive permeability and efflux transporters emerged as key drivers of intestinal excretion in rats. We also demonstrated that modulating a single functional group can alter the clearance pathways between intestinal and biliary excretion. The insights into intestinal excretion as a major clearance pathway for metabolically stable small-molecule drugs provide a more comprehensive understanding for drug clearance and offer new considerations for drug design and pharmacokinetic assessment.