Net Renal Drug Secretion Critically Requires Significant Contribution of Basal Uptake Transporters: Perspective From Mechanistic Kidney Model Simulation and Integration of Clinical and In Vitro Data.

Renal clearance (CLr) is the net outcome of glomerular filtration, secretion, and reabsorption, which makes the quantitative requirements for net renal secretion difficult to infer from simple clearance models. Using a mechanistic kidney model (MechKiM), we simulated blood-referenced CLr (CLr,b) for 30,000 virtual drugs (neutral, monoanionic, and monocationic) under continuous infusion and across all eight combinations of three proximal-tubule transporters (basal uptake, basal efflux, apical efflux). Net renal secretion (clearance ratio CR = CLr,b/(fu,b × GFR) > 1.5, where fu,b and GFR are the unbound fraction in blood and the glomerular filtration rate) occurred only when basal uptake transport was present; apical efflux alone produced proximal secretion that was offset by downstream reabsorption, yielding no net secretion. In the scenario where all three transporters were present within the MechKiM framework, five quantitative criteria distinguished secretion-type drugs, including basal transporter-mediated uptake (> 4.2 L/h) and its fractional contribution to total basal uptake (> 94% for non-cationic compounds). Clinical CLr,p (plasma-referenced CLr) versus in vitro uptake-transporter data (n = 217) and published MechKiM-PBPK models (n = 19, typically assigning > 99% of basal uptake to transporters) were consistent with these findings. A sufficient contribution of basal uptake transporters in the proximal tubule is essential for observing net renal secretion. This study provides quantitative, in vitro-translatable criteria to anticipate renal secretion and transporter-mediated drug-drug interaction liability.