Usefulness of A Model-Based Approach for Estimating In Vitro P-Glycoprotein Inhibition Potency in a Transcellular Transport Assay

Abstract In vitro half-maximal inhibitory concentration (IC 50 ) is a key parameter for accurately predicting the potential risk for P-glycoprotein (P-gp)–mediated drug–drug interactions. We aimed to compare the IC 50 values estimated by different approaches and determine the usefulness of model-based approaches. Transcellular transport of digoxin across Caco-2 monolayer was investigated using various concentrations of P-gp inhibitors, quinidine, verapamil, and zosuquidar. To calculate IC 50 values, 3 traditional parameters were used: apical-to-basal (AtoB) and basal-to-apical (BtoA) clearance (CL) with inhibitors (CL AtoB,i and CL BtoA,i ) and the difference between the efflux ratios (ERs) with P-gp inhibitors (ER i ) and those under complete P-gp inhibition [ER (−P-gp) ]. Furthermore, a new model-based approach was applied that uses the difference between the reciprocals of CL AtoB with P-gp inhibitors (1/CL AtoB,i ) and those under complete P-gp inhibition [1/CL AtoB(−P-gp) ] as parameters. IC 50 values obtained from 2 model-based approaches [ER i  − ER (−P-gp) and 1/CL AtoB,i  − 1/CL AtoB(−P-gp) ] were comparable, whereas 2.6- to 6.6-fold larger IC 50 values were estimated from empirical approaches (CL AtoB,i and CL BtoA,i ). The reason for such difference in IC 50 values is that indicators for model-based approaches, but not empirical approaches, directly reflect the P-gp function. Our new approach [1/CL AtoB,i  − 1/CL AtoB(−P-gp) ] based on only AtoB transcellular transport could substitute for current estimation methods using ER.