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

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.

Figure 1

Structural formulae of the new glucocorticoid fluticasone furoate in comparison with fluticasone propionate and mometasone furoate.

Figure 2

Relationship between the relative receptor affinities (RRA) of glucocorticoids and their lipophilicity expressed as relative retention times (k'). The reference glucocorticoid was dexamethasone for RRA and dexamethasone-21-isonicotinate for k'. Coefficient of correlation was r = 0.982 and the correlation was statistically significant (p ≤ 0.0001). Symbols used: filled black squares: glucocorticoids without ester function at C21 open white circles: glucocorticoids esterified at C21. * RRA determined in our own experiments, all other RRAs were obtained from [5, 16]. Abbreviations: Amcinonide (Amci), Dexamethasone (Dexa), Dexamethasone-21-isonicotinate (21-DIN), Flunisolide (Fluni), Fluticasone propionate (FP), Fluticasone furoate (FF), Mometasone (M), 6β-Hydroxy-Mometasone furoate (6OH-MF), Mometasone furoate (MF), Budesonide (Bud), Ciclesonide (Cicle), desisobutyryl Ciclesonide (des-Cicle), Beclomethasone-17,21-dipropionate (BDP), Beclomethasone-17-monopropionate (17-BMP), Beclomethasone-21-monopropionate (21-BMP), Prednisolone-21-propionate (21-PP).

Figure 3

Stability of fluticasone furoate (FF) in human lung tissue suspensions of 37°C over 24 hours. Symbols represent the mean and mean deviation of the mean of four independent series of experiments. One incubation mixture contained the esterase inhibitor dichlorvos to determine a potential esterase mediated decomposition of the parent compound. No statistically significant differences between FF concentrations in the presence or absence of dichlorvos were observed at any of the analysed time points.

Figure 4

Control experiment for non-specific adsorption of glucocorticoids to incubation vials. The respective compounds were incubated in glass vials over 480 min at 37°C. The concentration in the supernatant was monitored. The decrease in concentrations of mometasone furoate (MF) indicated the degradation process of the compound. No adsorption was seen for fluticasone propionate (FP) and fluticasone furoate (FF). The columns represent the mean and mean deviation of the mean from triplicate experiments.

Figure 5

Comparison of concentrations of fluticasone furoate (FF), fluticasone propionate (FP) and mometasone furoate (MF) in human lung tissue. The columns represent the mean and mean deviation of the mean from four independent experiments. The left columns represent the compound concentration in tissue before incubation in human plasma. This tissue binding of FF was statistically significantly higher compared to FP (p ≤ 0.001) and MF (p ≤ 0.01). The right columns display the glucocorticoid concentrations remaining in the lung tissue after one hour equilibration with human plasma at 37°C. Remaining concentrations of FP and FF were not different while statistically significantly lower concentrations of MF were retained in the tissue compared to FF (p ≤ 0.01) and FP (p ≤ 0.001).