Assessment of Human Renal Transporter Based Drug-Drug Interactions Using Proximal Tubule Kidney-Chip

Abstract

AbstractStudy of renal transporters is crucial for understanding drug disposition and toxicity, and more importantly, predicting potential drug-drug interactions (DDIs). However, conventional in vitro models often fail to predict renal transporter activity and are not scalable to a predictive clinical outcome due to in vitro-in vivo discrepancy. Here, we successfully developed a human Proximal Tubule Kidney-Chip model that emulated in vivo renal physiology and function to assess renal transporter-based DDIs. Active and improved functionality of key renal transporters including p-glycoprotein (P-gp), multidrug and toxin extrusion (MATE) 1 and 2-K, organic anion transporter (OAT) 1 and 3, and organic cation transporter (OCT) 2 were demonstrated using appropriate probe substrates in Kidney-Chips compared to transwell controls. Moreover, comparative transcriptomic analysis revealed that key efflux and uptake transporters were expressed significantly higher in the Kidney-Chip compared to the transwell. Additionally, key parameters obtained from substrate-inhibitor interactions in the model were used to predict clinical DDIs as well as clearance values, which were closer to in vivo clearances. Overall, these results support that the human Proximal Tubule Kidney-Chip can reliably assess the role of human renal transporters in drug disposition and drug interactions, providing a critical tool to assess renal transport in vitro.