Determinants of Intestinal Availability for P-glycoprotein Substrate Drugs Estimated by Extensive Simulation With Mathematical Absorption Models

Abstract

In this study, intestinal drug-drug interactions (DDIs) for substrate drugs of P-glycoprotein were simulated extensively using the extended Q_Gut model and translocation model to explore the determinants of DDI. The results of analyses using both models suggested that permeability and active efflux clearance were the major factors that influenced the fraction absorbed (F_A). The results of simulation for 100 virtual drugs in which parameters were generated considering the actual values of commercially available drugs suggested that the ratio of the pH-corrected passive permeability to the intrinsic efflux clearance (P_u/CL_eff) relative to that of digoxin would be a useful and quantitative index of P-glycoprotein (P-gp)-mediated DDI risk at lower doses. At higher doses, such as 100 mg, the risk of P-gp-mediated DDI would be significantly reduced because of saturation of P-gp efflux. The simulation suggested that although drugs with lower permeability were more susceptible, even drugs with higher permeability than metoprolol, a representative highly permeable drug, such as BCS class 1 and 2, may experience DDIs owing to P-gp inhibition. Overall, this study demonstrated the usefulness of mathematical intestinal models when only limited observational data are available.

Keywords: P-glycoprotein; drug–drug interaction; intestinal absorption; modeling and simulation; physiologically based pharmacokinetic model; substrate drug.