Differences in Endogenous Esterification and Retention in the Rat Trachea between Budesonide and Ciclesonide Active Metabolite

Abstract

ABSTRACT:The airway retention of inhaled glucocorticosteroids (GCs) depends largely on their lipophilicity. Inhaled budesonide (BUD) becomes highly lipophilic reversibly by the formation of esters acting as a reservoir of active BUD. Ciclesonide (CIC) was also reported to form esters after hydrolysis to active metabolite (CIC-AM). We have investigated lipophilicity and airway retention of BUD, CIC/ CIC-AM, fluticasone propionate (FP), and mometasone furoate (MF), and compared esterification of BUD and CIC-AM and its contribution to GC airway retention. Rat tracheas were preincubated with the esterification inhibitor cyclandelate or vehicle. A 3 H-GC (ϳ10 ؊7 M: BUD, CIC, CIC-AM, FP, MF) was added for 20 min.After incubation, one half of the trachea was used for analysis of GC uptake and the other to analyze GC release during 3 h in drug-free medium. GC species in trachea halves were analyzed by radiochromatography. At 20 min, the uptake of BUD was similar to that of CIC/CIC-AM; however, the BUD-ester pool was 9-fold greater (p < 0.01). BUD overall retention in trachea at 3 h was greater than that of other GCs (p < 0.01), and the BUD-ester pool was 3-fold greater than the CIC-AM-ester pool (p < 0.01). Cyclandelate decreased the initial BUD-and CIC-AM-ester pools (p < 0.01), and reduced the overall retention of BUD at 3 h (p < 0.01) but not of CIC-AM. Thus, BUD becomes esterified in the airways more promptly and to a greater extent than CIC-AM, and BUD esterification prolongs BUD airway retention. In contrast, airway retention of CIC-AM and CIC seems to be determined mainly by their lipophilicity, similar to FP and MF, which are not esterified.

Dissolution in nasal fluid, retention and anti‐inflammatory activity of fluticasone furoate in human nasal tissue ex vivo

“…Thus, highest concentrations of TCA and Bud were measured. These TCA concentrations determined in the drug preparation were in excellent agreement with previously published data of the compounds' water solubility at 37 °C while the solubility of Bud was clearly higher than reported previously [28–31]. The latter might be due to the composition of the drug formulation, which might enhance the drug solubility by the use of certain excipients.…”

Different Nebulized Budesonide Dosing Regimens in a Mouse Model of Chronic Asthma

“…It has been shown that the duration of action of budesonide, when compared with other inhaled corticosteroids, is longer when it is esterified. Lexmüller et al (12) demonstrated that the elimination of budesonide from the trachea and the main stem bronchus was 35-fold slower than that for fluticasone propionate. Moreover, budesonide overall retention in trachea at 3 hours was greater than that of other corticosteroids, and the budesonideester pool was 3-fold greater than the cyclesonide ester pool.…”

Tissue Accumulation Kinetics of Ciclesonide‐active Metabolite and Budesonide in Mice

“…For BUD, rates of esterification and/or hydrolysis in rat lung and trachea were shown to differ between the luminal versus vascular side of the airways [6]. In rat trachea, also a difference in the rate of net ester formation between BUD and des-CIC was shown [7]. This might be explained by different enzymes regulating esterification and/or hydrolysis of these compounds but may also be due to molecular structure differences because hydrolysis of steroid esters is a relatively stereoselective process [18].…”