title: 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 (IC50) is a key parameter for accurately predicting the potential risk for P-glycoprotein (P-gp)--mediated drug--drug interactions. We aimed to compare the IC50 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 IC50 values, 3 traditional parameters were used: apical-to-basal (AtoB) and basal-to-apical (BtoA) clearance (CL) with inhibitors (CLAtoB,i and CLBtoA,i) and the difference between the efflux ratios (ERs) with P-gp inhibitors (ERi) 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 CLAtoB with P-gp inhibitors (1/CLAtoB,i) and those under complete P-gp inhibition [1/CLAtoB(-P-gp)] as parameters. IC50 values obtained from 2 model-based approaches [ERi - ER(-P-gp) and 1/CLAtoB,i - 1/CLAtoB(-P-gp)] were comparable, whereas 2.6- to 6.6-fold larger IC50 values were estimated from empirical approaches (CLAtoB,i and CLBtoA,i). The reason for such difference in IC50 values is that indicators for model-based approaches, but not empirical approaches, directly reflect the P-gp function. Our new approach [1/CLAtoB,i - 1/CLAtoB(-P-gp)] based on only AtoB transcellular transport could substitute for current estimation methods using ER.
authors: Pharmacokinetics and Non-Clinical Safety, Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan.
authors: Wataru
authors: W
authors: Kishimoto
authors: Pharmacokinetics and Non-Clinical Safety, Nippon Boehringer Ingelheim Co., Ltd., Kobe, Japan. Electronic address: naoki.ishiguro@boehringer-ingelheim.com.
authors: Naoki
authors: N
authors: Ishiguro
authors: Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
authors: Eva
authors: E
authors: Ludwig-Schwellinger
authors: Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
authors: Thomas
authors: T
authors: Ebner
authors: Laboratory of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
authors: Kazuya
authors: K
authors: Maeda
authors: Sugiyama Laboratory, RIKEN Innovation Center, Research Cluster for Innovation, RIKEN, Yokohama, Japan.
authors: Yuichi
authors: Y
authors: Sugiyama
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018938:Caco-2 Cells; D004077:Digoxin / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions / Q000502:physiology; D006801:Humans; D008954:Models, Biological; D057900:Transcytosis / Q000187:drug effects* / Q000502:physiology*; D014700:Verapamil / Q000378:metabolism / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004077:Digoxin; D014700:Verapamil
keywords: ABC transporters; Caco-2 cells; P-glycoprotein; drug interactions; efflux pumps; inhibition; mathematical models; membrane transport/transporters; pharmacokinetics; transporters