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  • Title: Differences in endogenous esterification and retention in the rat trachea between budesonide and ciclesonide active metabolite.
    Author: Lexmüller K, Gullstrand H, Axelsson BO, Sjölin P, Korn SH, Silberstein DS, Miller-Larsson A.
    Journal: Drug Metab Dispos; 2007 Oct; 35(10):1788-96. PubMed ID: 17627977.
    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 ( approximately 10(-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.
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