Prolonged airway activity and improved selectivity of budesonide possibly due to esterification

We addressed the question of whether the prolonged local retention of the glucocorticoid (GC) budesonide (BUD) within airway tissue, due to reversible fatty acid esterification, is associated with protracted topical anti-inflammatory activity and improved airway selectivity, when compared with fluticasone propionate (FP). BUD or FP at 25 nmol/kg was administered intratracheally or subcutaneously to adrenalectomized rats, followed by lipopolysaccharide (LPS) intratracheal instillation. The trachea and main bronchi were lavaged 6 h after LPS, and tumor necrosis factor-alpha (TNF-alpha) concentration and cell number in the lavage fluid were measured. Instilled 1 h before LPS, both GCs reduced TNF-alpha by 70% (p < 0.05) and mononuclear cells by 55% (p < 0.01), with no reduction in neutrophils. Instilled 6 h before LPS, a significant reduction of TNF-alpha (59%, p < 0.02) and mononuclear cells (47%, p < 0.05) was achieved only with BUD. After subcutaneous administration, no significant effects were observed. BUD did not exert higher systemic activity than FP, measured as plasma corticosterone suppression. In conclusion, BUD exerted a more prolonged topical anti-inflammatory activity, and a higher airway selectivity than FP, possibly because of its reversible fatty acid esterification within airway tissue. This may contribute to the high efficacy and safety of BUD in asthma, even with once-daily inhalation.