title: Evaluation of P-Glycoprotein Inhibitory Potential Using a Rhodamine 123 Accumulation Assay.
abstract: In vitro evaluation of P-glycoprotein (P-gp) inhibitory potential is now a regulatory issue during drug development, in order to predict clinical inhibition of P-gp and subsequent drug-drug interactions. Assays for this purpose, commonly based on P-gp-expressing cell lines and digoxin as a reference P-gp substrate probe, unfortunately exhibit high variability, raising thus the question of developing alternative or complementary tests for measuring inhibition of P-gp activity. In this context, the present study was designed to investigate the use of the fluorescent dye rhodamine 123 as a reference P-gp substrate probe for characterizing P-gp inhibitory potential of 16 structurally-unrelated drugs known to interact with P-gp. 14/16 of these P-gp inhibitors were found to increase rhodamine 123 accumulation in P-gp-overexpressing MCF7R cells, thus allowing the determination of their P-gp inhibitory potential, i.e., their half maximal inhibitor concentration (IC50) value towards P-gp-mediated transport of the dye. These IC50 values were in the range of variability of previously reported IC50 for P-gp and can be used for the prediction of clinical P-gp inhibition according to Food and Drug Administration (FDA) criteria, with notable sensitivity (80%). Therefore, the data demonstrated the feasibility of the use of rhodamine 123 for evaluating the P-gp inhibitory potential of drugs.
authors.affiliation: Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France. elodie.jouan@gmail.com.
authors.forename: Elodie
authors.initials: E
authors.lastname: Jouan
authors.affiliation: Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France. marc.levee@free.fr.
authors.forename: Marc
authors.initials: M
authors.lastname: Le Vée
authors.affiliation: Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France. abdullah.mayati@univ-rennes1.fr.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Mayati
authors.affiliation: Centre de Pharmacocinétique, Technologie Servier, 25-27 Rue Eugène Vignat, 45000 Orléans, France. claire.denizot@servier.com.
authors.forename: Claire
authors.initials: C
authors.lastname: Denizot
authors.affiliation: Centre de Pharmacocinétique, Technologie Servier, 25-27 Rue Eugène Vignat, 45000 Orléans, France. yannick.parmentier@servier.com.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Parmentier
authors.affiliation: Institut de Recherches en Santé, Environnement et Travail (IRSET), UMR INSERM U1085, Faculté de Pharmacie, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France. olivier.fardel@univ-rennes1.fr.|Pôle Biologie, Centre Hospitalier Universitaire, 2 rue Henri le Guilloux, 35033 Rennes, France. olivier.fardel@univ-rennes1.fr.
authors.forename: Olivier
authors.initials: O
authors.lastname: Fardel
keywords: P-glycoprotein; digoxin; drug–drug interactions; inhibition; rhodamine 123