title: Establishment of in vitro P-glycoprotein inhibition assay and its exclusion criteria to assess the risk of drug-drug interaction at the drug discovery stage.
abstract: The decision tree to determine whether the P-glycoprotein (P-gp)/multidrug resistance protein 1 (MDR1)-mediated drug-drug interaction (DDI) study is recommended has been proposed by the International Transporter Consortium. We, therefore, designed an in vitro P-gp inhibition assay and determined the appropriate risk criteria for P-gp-mediated DDI at the drug discovery stage. Effects of P-gp inhibitors on digoxin transport across a monolayer of MDR1-expressing cells were examined. The IC(50) (half-maximal inhibitory concentration) values generated from the efflux ratio (ER) were smaller than those generated from basolateral-to-apical directional apparent permeability. The difference in IC(50) values was kinetically described in a compartment model analysis. This analysis indicated that ER is a highly sensitive parameter that can be used for the degree of P-gp inhibition. Considering IC(50) values and the increase in digoxin exposure in clinical DDI studies, the risk criteria of [I(2)]/IC(50) = 30 ([I(2)], theoretically maximal gastrointestinal concentration) was the optimal cutoff value to predict a clinically relevant DDI. We also investigated whether the IC(50) value itself is applicable to assess the DDI risk. In conclusion, compounds with IC(50) values less than 2 μM exhibit high risk for P-gp-mediated DDIs. However, compounds with IC(50) values greater than or equal to 2 μM are inconclusive because clinical doses should be considered for the precise DDI risk assessment.
authors.affiliation: Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., Osaka, Japan. Sugimoto_Hiroshi1@takeda.co.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Miho
authors.initials: M
authors.lastname: Tachibana
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Niwa
authors.forename: Hideki
authors.initials: H
authors.lastname: Hirabayashi
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Amano
authors.forename: Toshiya
authors.initials: T
authors.lastname: Moriwaki
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000818:Animals; D004077:Digoxin / Q000493:pharmacokinetics; D055808:Drug Discovery; D004347:Drug Interactions; D006801:Humans; D066298:In Vitro Techniques; D020128:Inhibitory Concentration 50; D018374:LLC-PK1 Cells; D013552:Swine
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004077:Digoxin