Quantitative analysis of the effect of controlled-release formulation on nonlinear gastrointestinal absorption of P-glycoprotein substrate talinolol using physiologically based pharmacokinetic absorption model

Abstract Oral absorption of talinolol, a substrate of P-glycoprotein (P-gp), from a sustained-release (SR) formulation was reportedly decreased compared to that from an immediate-release (IR) formulation. The aim of this study was to predict and understand the effect of controlled-release formulation on the oral absorption of P-gp substrates by developing a physiologically based pharmacokinetic (PBPK) absorption model incorporating multiple kinetic parameters obtained from in vitro studies, using talinolol as a model substrate. Simulation analysis using the developed PBPK absorption model indicated that the clinically observed marked decrease in the plasma concentration of talinolol administered in an SR formulation occurs because the epithelial concentration of talinolol in this case is lower than the K m value for P-gp. In other words, a decrease in the epithelial concentration of talinolol due to SR dosage formulation may lead to greater impact of P-gp-mediated drug efflux, resulting in decreased intestinal drug absorption, whereas an increase in the epithelial concentration of talinolol after administration in IR formulation may lead to saturation of P-gp. In conclusion, our strategy of simulation with a PBPK absorption model indicates that nonlinear saturable intestinal absorption characteristics can make SR formulations of P-gp substrates ineffective by decreasing the drug absorption.