title: Differences in endogenous esterification and retention in the rat trachea between budesonide and ciclesonide active metabolite.
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.
authors.affiliation: AstraZeneca Research and Development Lund, Lund, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Lexmüller
authors.forename: Helena
authors.initials: H
authors.lastname: Gullstrand
authors.forename: Bengt-Olof
authors.initials: BO
authors.lastname: Axelsson
authors.forename: Petter
authors.initials: P
authors.lastname: Sjölin
authors.forename: Solange H
authors.initials: SH
authors.lastname: Korn
authors.forename: David S
authors.initials: DS
authors.lastname: Silberstein
authors.forename: Anna
authors.initials: A
authors.lastname: Miller-Larsson
mesh_terms: D000818:Animals; D019819:Budesonide / Q000378:metabolism*; D003495:Cyclandelate / Q000494:pharmacology; D004951:Esterification / Q000187:drug effects; D005938:Glucocorticoids / Q000378:metabolism*; D008297:Male; D011282:Pregnenediones / Q000378:metabolism*; D051381:Rats; D011914:Rats, Inbred BN; D012995:Solubility; D014132:Trachea / Q000378:metabolism*
chemical_list: D005938:Glucocorticoids; D011282:Pregnenediones; D003495:Cyclandelate; D019819:Budesonide; C120481:ciclesonide