The impact of drug clearance on duration of action of corticosteroids

Amir Hakim, Peter J Barnes, Ian M Adcock, Omar S Usmani

Corticosteroids (CS) are widely used in the treatment of asthma and chronic obstructive pulmonary disease. Following inhalation, corticosteroids are subjected to drug clearance within the lungs. Their duration of action is dictated by their physiochemical properties, which subsequently impacts on their binding and activation of the glucocorticoid receptor (GR), essential for corticosteroid function. Upon activation, GR translocates into the nucleus, where it reduces expression of pro-inflammatory markers, such as CXCL8. We hypothesised that fluticasone furoate (FF), a once-daily CS that has superior affinity and a slower rate of dissociation from GR than budesonide (BUD) and fluticasone propionate (FP) will maintain its action and function following a 20h washout period. The effects of BUD, FP and FF on GR nuclear translocation over a 24h time-course was examined in U937 monocytes. Importantly, we compared the effects of a 20h washout on GR nuclear localisation and suppression of CXCL8 following treatment with CS for 4h. Statistical analysis was performed using non-parametric analyses and results presented as meanĀ±SEM. Treatment with BUD, FP and FF significantly induced GR nuclear translocation at 24h. Importantly, a 20h washout following a 4h treatment period reduced BUD- and FP-induced GR nuclear localisation to basal levels, whereas FF maintained similar levels of GR nuclear translocation. A corresponding difference in CXCL8 suppression was also observed following the 20h washout period. Exposure of cells to FF for 4h (followed by 20h washout) was as effective as continued exposure for 24h.

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