title: A transcellular assay to assess the P-gp inhibition in early stage of drug development.
abstract: To provide a fast assessment in predicting P-gp-mediated DDI risk during early stage of drug development, a transcellular P-gp inhibition assay using two concentrations is presented in the present study. The efflux ratios of loperamide in the presence of forty-five commercial compounds at two concentrations were measured and compared to that of six concentrations in human P-gp cDNA-expressing LLC-PK1 cells (LLC-MDR1). The inhibition potency calculated from the change on the efflux ratio (ER) and on the net secretory flux (NSF) of loperamide was investigated. The P-gp inhibition potency was defined as potent (IC50 < 1 µM), moderate (1 µM < IC50 < 10 µM), or weak (IC50 > 10 µM). The results using 1 µM and 10 µM of inhibitor concentrations provided the best correlation and are most consistent with those generated from a 6-point approach.
authors.affiliation: Drug Metabolism and Pharmacokinetics, Biopharmaceutical Assessments Core Function Unit, Eisai Inc., USA. jesse_taur@eisai.com
authors.forename: Jan-Shiang
authors.initials: JS
authors.lastname: Taur
authors.forename: Edgar L
authors.initials: EL
authors.lastname: Schuck
authors.forename: Nancy Y
authors.initials: NY
authors.lastname: Wong
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D004347:Drug Interactions; D018374:LLC-PK1 Cells; D008139:Loperamide / Q000493:pharmacokinetics; D013552:Swine
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008139:Loperamide