Fluticasone furoate, a novel corticosteroid, maintains glucocorticoid receptor nuclear localisation for 24 hours after washout in monocytes

Background: Fluticasone furoate (FF) is a novel corticosteroid (CS) under development for inhaled once daily administration for chronic obstructive pulmonary disease and asthma. CS act via binding to the glucocorticoid receptor (GR). Upon activation, GR translocates into the nucleus, an essential prerequisite for CS function. In dose-ranging studies in asthmatics, FF had 24 hour (h) duration of efficacy. We hypothesized, therefore, that the sustained activity of FF is due to prolonged GR nuclear translocation. Method: The effects of FF on GR nuclear translocation over a 24h time-course was examined in U937 monocytes. In addition, we compared the effect of a 20h washout on GR nuclear localisation following treatment with FF for 4h. Statistical analysis was performed using Kruskal-Wallis analysis and results represented as mean±SEM. Results: FF significantly induced GR nuclear translocation in a time- (2-24hr) and concentration- (10 –11 –10 –7 M) dependent manner (p –7 M) significantly increased nuclear GR levels at 4h (5.4±0.57 fold increase, p –7 M) treatment as seen with continual FF exposure (5.7±0.85 versus 6.6±0.92 fold increase, p=ns). Conclusions: FF induced GR nuclear translocation in a time and concentration dependent manner. Exposure of cells to FF for 4h was as effective as continued exposure for 24h. Funded by GlaxoSmithKline.