Human receptor kinetics and lung tissue retention of the enhanced-affinity glucocorticoid fluticasone furoate

Anagnostis Valotis,Petra Högger

doi:10.1186/1465-9921-8-54

Abstract

Fluticasone furoate (FF) – USAN approved name, a new topically active glucocorticoid has been recently identified. The aim of this study was to characterise the binding affinity of this compound to the human lung glucocorticoid receptor in relation to other glucocorticoids. Additionally, we sought to determine the binding behaviour of fluticasone furoate to human lung tissue. The glucocorticoid receptor binding kinetics of fluticasone furoate revealed a remarkably fast association and a slow dissociation resulting in a relative receptor affinity (RRA) of 2989 ± 135 with reference to dexamethasone (RRA: 100 ± 5). Thus, the RRA of FF exceeds the RRAs of all currently clinically used corticosteroids such as mometasone furoate (MF; RRA 2244), fluticasone propionate (FP; RRA 1775), ciclesonide's active metabolite (RRA 1212 – rat receptor data) or budesonide (RRA 855). FP and FF displayed pronounced retention in human lung tissue in vitro. Lowest tissue binding was found for MF. There was no indication of instability or chemical modification of FF in human lung tissue. These advantageous binding attributes may contribute to a highly efficacious profile for FF as a topical treatment for inflammatory disorders of the respiratory tract.

Highlights

A new topically active glucocorticoid, fluticasone furoate (FF, GW685698X), has been recently identified (Figure 1) and is being progressed for the treatment of respiratory diseases
Receptor binding kinetics and relative receptor affinity of fluticasone furoate (FF) The receptor binding kinetics to the human lung glucocorticoid receptor revealed that the association kinetics of fluticasone furoate (FF) was distinctly different from those of fluticasone propionate (FP) and mometasone furoate (MF) (Table 1)
The association rate constant of Fluticasone furoate (FF) was statistically significantly higher compared to both MF and FP; the specific binding to the receptor occurred more rapidly and to a higher extent compared with all other glucocorticoids

Summary

Introduction

A new topically active glucocorticoid, fluticasone furoate (FF, GW685698X), has been recently identified (Figure 1) and is being progressed for the treatment of respiratory diseases. Fluticasone furoate (FF) shares structural similarities with fluticasone propionate (FP) with the exception of the substitution of the 17-α hydroxyl group. While this position is esterified with propionic acid in FP, FF carries a 2-furoate ester moiety. We previously described the receptor binding affinity of FP and MF as well as their retention in lung tissue in vitro [1,2,3,4]. Both FP and MF have high affinities for the human lung glucocorticoid receptor. The relative receptor affinity (RRA) of FP is about 1800 compared to the reference compound dexamethasone (RRA= 100), the RRA of MF is about 2250

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