Differences in endogenous esterification and retention in the rat trachea between budesonide and ciclesonide active metabolite.
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.
Lexmüller
Kristina
K
AstraZeneca Research and Development Lund, Lund, Sweden.
Gullstrand
Helena
H
Axelsson
Bengt-Olof
BO
Sjölin
Petter
P
Korn
Solange H
SH
Silberstein
David S
DS
Miller-Larsson
Anna
A
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*
D005938:Glucocorticoids; D011282:Pregnenediones; D003495:Cyclandelate; D019819:Budesonide; C120481:ciclesonide