Aims: Evidence is accumulating that budesonide (BUD) forms intracellular esters in airways. which may affect both duration of action and therapeutic ratio of this drug. The aim of the present paper is to review the preclinical and human experimental evidence supporting the esterification of BUD, and to discuss the clinical implications this may have on asthma and rhinitis treatment.
Results: After inhalation, intact BUD binds primarily to available steroid receptors, and mainly excess (unbound) BUD is esterified. Esterification of BUD is a rapid process: within 20 minutes of inhalation in the rat of radiolabeled BUD, approximately 80% of radioactivity within the trachea and main bronchi was associated with BUD esters, primarily BUD oleate. After 4 hours, the proportion of BUD esters/total cellular BUD was typically 40 to 50% for lung, 70 to 90% for trachea, and only 10 to 15% for peripheral muscle. Comparative in vitro and in vivo studies have shown that esterification prolongs BUD's anti-inflammatory activity longer than that of corticosteroids that can not form esters. Clinical studies have confirmed the prolonged presence of BUD esters, as well as intact BUD, in human airway tissues: 6 hours postdosing, nasal biopsy concentrations of intact BUD were >10-fold greater than those of fluticasone propionate and at 24 hours BUD was detectable in threefold more biopsies than fluticasone propionate. The impact of esterification on airway selectivity of BUD has also been demonstrated in vivo and using pharmacokinetic/pharmacodynamic models.
Conclusions: BUD is retained in airways as esters, a novel kinetic mechanism for synthetic glucocorticoids. In preclinical studies this esterification is correlated to a prolonged local tissue binding and efficacy, which is not found when the esterification is inhibited by an esterification blocker. Because less esters are formed in the systemic compartment than in airways/lung, the local benefit:systemic risk ratio may also be improved by this mechanism. BUD possesses favorable clinical properties, including its approved once-daily efficacy in asthma, which is probably in part attributable to esterification. However, a direct proof of the latter in patients requires effective and safe inhibitors of the esterification, which are not yet available. Therefore, evidence to support the therapeutic impact of esterification is still circumstantial.