REVERSIBLE FATTY-ACID CONJUGATION OF BUDESONIDE - NOVEL MECHANISM FORPROLONGED RETENTION OF TOPICALLY APPLIED STEROID IN AIRWAY TISSUE

A high airway concentration might be required for the antiasthmatic ef ficacy of inhaled glucocorticosteroids (GCS). The topical uptake and r etention of GCS in airway tissue were compared for GCS of the inhaled type [budesonide (BUD), fluticasone propionate (FP), and beclomethason e dipropionate (BDP)] and of the noninhaled type (dexamethasone and hy drocortisone), H-3-labeled GCS solutions were administered into rat ai rways by either perfusion of trachea in vivo, intratracheal instillati on, or inhalation. Radioactivity was determined in the airway tissue, lung parenchyma, and plasma 20 min to 24 hr after exposure. Ethanol ex tracts of exposed tracheas were analyzed by HPLC. Exposed tracheas wer e also incubated in vitro in buffer, and the released radioactivity wa s analyzed by HPLC. BUD, FP, and BDP were equally well taken up into t he airway tissue; their uptake was 25-130 times greater than that of d examethasone and hydrocortisone, BUD was shown to form very lipophilic intracellular fatty acid esters (at carbon 21) in the airway and lung tissue after topical application. In large airways 20 min after admin istration, approximately 70-80% of retained BUD was conjugated. BUD st ored in esterified form in the tissue was retained in large airways fo r a prolonged time, compared with FP and BDP, which do not form such c onjugates. The fatty acid conjugation of BUD is reversible in vivo; BU D conjugates are gradually hydrolyzed and free BUD is regenerated. Thi s reversible conjugation may improve airway selectivity, as well as pr olong the local anti-inflammatory action of BUD in the airways and mig ht be one explanation for why BUD is efficacious in the treatment of m ild asthma when inhaled once daily.