Evaluating the Optimal In Vitro Transport Conditions for PBPK Modeling of OAT1 Involvement in Renal Drug Clearance

Abstract

Predicting pharmacokinetics of drug transporter substrates using PBPK modeling requires accurate transport kinetics in vitro. It is unclear what effect incubation time has on transport kinetics under initial zero-trans conditions. In this study, the influence of incubation time on OAT1 transport kinetics and its influence on PBPK predictions was examined. The in vitro intrinsic uptake clearance (CLint) of para-aminohippurate (PAH) by OAT1 stably expressed in CHO cells was determined at different time points, from initial-rate to steady-state, under zero-trans or equilibrium exchange conditions. The Simcyp Simulator was used to simulate PAH pharmacokinetics using the different CLint values obtained. The data show that transport kinetics and inhibition potency are both influenced by the in vitro incubation time used. This results in modest to large differences in PBPK predictions in the involvement of OAT1 in pharmacokinetics and DDIs.