Uptake and metabolism of ciclesonide and retention of desisobutyryl-ciclesonide for up to 24 hours in rabbit nasal mucosa.
BACKGROUND
The nasal tissue uptake and metabolism of ciclesonide, a new-generation corticosteroid under investigation for treatment of allergic rhinitis, to its active metabolite, desisobutyryl-ciclesonide (des-CIC), was evaluated when administered to rabbits in a hypotonic versus an isotonic ciclesonide suspension. Nasal mucosa extracts from normal Japanese white rabbits were evaluated by high-performance liquid chromatography with tandem mass spectrometry detection after a single 143-mug dose of ciclesonide. Retention and formation of fatty acid conjugates of des-CIC were also measured in nasal mucosa extracts postadministration of a hypotonic ciclesonide suspension (143-mug single dose).


RESULTS
Versus an isotonic suspension, the hypotonic suspension achieved higher concentrations of des-CIC (5.6-fold, 11.4-fold, and 13.4-fold; p < 0.05 for all) and ciclesonide (25.3-fold, 34.2-fold [p = not significant], and 16-fold [p < 0.05]) at 30, 120, and 240 min postadministration. Additionally, when administered via a hypotonic suspension, des-CIC was retained up to 24 h postadministration (45.46 pmol/g tissue). Highest concentration of major fatty acid ester conjugate, des-CIC-oleate, was detected in nasal mucosa at 8 h postadministration.


CONCLUSIONS
These data suggest that a hypotonic ciclesonide suspension provides higher intracellular concentrations of des-CIC up to 24 h, thereby providing a rationale for investigation of ciclesonide as a convenient once-daily nasal spray for treatment of allergic rhinitis.
Sato
Hideyuki
H
Teijin Institute for Biomedical Research, TEIJIN Pharma Limited, Asahigaoka, Hino, Tokyo, Japan. hid.satou@teijin.co.jp <hid.satou@teijin.co.jp>
Nave
Ruediger
R
Nonaka
Takashi
T
Yoshihisa
Nishibe
N
Atsuhiro
Nagano
N
Mochizuki
Tsutomu
T
Takahama
Shigehiro
S
Kondo
Shiro
S
Wingertzahn
Mark
M
D000281:Administration, Intranasal; D000818:Animals; D018926:Anti-Allergic Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D004334:Drug Administration Schedule; D004952:Esters / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D007038:Hypotonic Solutions; D007552:Isotonic Solutions; D008297:Male; D009297:Nasal Mucosa / Q000378:metabolism*; D011282:Pregnenediones / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics*; D011817:Rabbits; D013535:Suspensions; D053719:Tandem Mass Spectrometry; D013997:Time Factors
D018926:Anti-Allergic Agents; D004952:Esters; D005227:Fatty Acids; D007038:Hypotonic Solutions; D007552:Isotonic Solutions; D011282:Pregnenediones; D013535:Suspensions; C494355:desisobutyrylciclesonide; C120481:ciclesonide