BINDING-KINETICS OF FLUTICASONE PROPIONATE TO THE HUMAN GLUCOCORTICOID RECEPTOR

Receptor-ligand interactions of fluticasone propionate (FP), a glucoco rticoid used for inhalation therapy,, were determined and compared wit h dexamethasone, budesonide, and beclomethasone-17-monopropionate, the active metabolite of beclomethasone dipropionate. Two approaches, eva luation of binding kinetics and competition assays, were applied to ob tain relative receptor affinities (RRAs) with dexamethasone as referen ce. A higher association I ate constant and a distinctly lower dissoci ation rate constant for FP compared with the other glucocorticoids res ulted in an equilibrium dissociation constant (K-d) of 0.49 nmol/l. K- d dexamethasone was 9.36 nmol/l; derived RRA of FP was 1910. The calcu lated half-time of the FP-receptor complex was 10 h, thus exceeding th e half-times of all other glucocorticoids as well as their RRAs. Compe tition assays clearly confirmed the rank order of the tested glucocort icoids, although RRAs were generally lower than those found in kinetic assays and strongly dependent on the assay conditions. The high recep tor affinity of FP is reflected by clinical trials demonstrating its s uperiority to other glucocorticoids. For therapeutic application, the long half-time of the FP-receptor complex should support the practical ity of longer dose-intervals.