An Unsupervised Approach for Predicting Transporter-Mediated Drug-Metabolite Interactions

Organic anion transporter 1 (OAT1) and 3 (OAT3) are multi-specific renal drug transporters that facilitate the uptake and clearance of a wide range of endogenous and exogenous molecules. While they’ve been extensively studied for their clinical role in drug disposition and potential drug-drug interactions (DDIs), their physiological role in regulating metabolism and systemic homeostasis is less understood. With the availability of new metabolomics data, we explore drug-metabolite interactions (DMIs) and their potential impacts on metabolic pathways through the use of chemical spaces presented herein and challenge the well established in silico virtual screening approach formulated under the assumption that structural similarity is necessary for a potential DDI. Overall, our analyses help elucidate the role of OAT-mediated drug-metabolite interactions in drug-induced metabolic dysregulation and provide insight into the unexplained side effects and toxicities from long-term drug treatment and/or polypharmacotherapy.