title: Evaluation of inhibitory potencies for compounds inhibiting P-glycoprotein but without maximum effects: f2 values.
abstract: In cell culture systems with aqueous buffers, concentration-response curves to lipophilic inhibitors are difficult to establish because plateau effects (Imax) are often not reached because of limited drug solubility. Consequently, the inhibitory potency of a compound will not be definable using IC50 values (concentration exerting 50% of Imax). Since alternative potency measures f2 values, the concentrations required to double baseline signals have been proposed. Using both methods, we reevaluated the concentration-response curves of calcein assays with 78 compounds in three different cell culture systems and found a close correlation between both methods (r(s) = 0.93-0.99, p < or = 0.0028). These findings suggest that f2 values are a valuable alternative to define rank orders of highly lipophilic inhibitors as a basis for the prediction of pharmacological interaction properties in clinical settings. Although it was only tested for inhibition of P-glycoprotein, it seems likely that this method may be transferred to other assays with other proteins.
authors.affiliation: Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany. johanna.weiss@med.uni-heidelberg.de
authors.forename: Johanna
authors.initials: J
authors.lastname: Weiss
authors.forename: Walter Emil
authors.initials: WE
authors.lastname: Haefeli
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001681:Biological Assay; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D042783:Endothelial Cells / Q000378:metabolism; D005452:Fluoresceins / Q000378:metabolism; D006801:Humans; D051379:Mice; D004364:Pharmaceutical Preparations; D012995:Solubility; D013552:Swine
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D005452:Fluoresceins; D004364:Pharmaceutical Preparations; C007740:fluorexon