In vitro metabolism of ciclesonide in human nasal epithelial cells.
Ciclesonide, a corticosteroid in development for allergic rhinitis, is converted to the pharmacologically active metabolite, desisobutyryl-ciclesonide (des-CIC), and des-CIC is subsequently esterified with fatty acids. Various experiments were performed to investigate ciclesonide metabolism in human nasal epithelial cells (HNEC). Human nasal epithelial cells were incubated with (a) 0.1 microM ciclesonide for 1 h and medium without ciclesonide for up to 24 h, (b) esterase inhibitors for 0.5 h followed by 5 microM ciclesonide for 6 h, or (c) 1 microM des-CIC for 6 h followed by medium without des-CIC for up to 24 h. Ciclesonide, des-CIC and des-CIC fatty acid conjugate concentrations were determined by high-performance liquid chromatography with tandem mass spectrometry. The amount of ciclesonide in HNEC decreased approximately 93-fold from 0.5 to 24 h. In contrast, des-CIC was present at constant levels throughout the post-treatment period. Furthermore, fatty acid conjugates of des-CIC were retained in HNEC up to 24 h post-treatment. Carboxylesterase and cholinesterase inhibitors decreased ciclesonide metabolism > or =50%. The total amounts of des-CIC fatty acid conjugates decreased and the extracellular amounts of des-CIC increased with time. In conclusion, ciclesonide was rapidly converted to des-CIC by carboxylesterases and cholinesterases, and des-CIC underwent reversible fatty acid conjugation in HNEC.
Sato
Hideyuki
H
Teijin Institute for Biomedical Research, Teijin Pharma Limited, Hino, Tokyo, Japan. hid.satou@teijin.co.jp
Nave
Ruediger
R
Nonaka
Takashi
T
Mochizuki
Tsutomu
T
Takahama
Shigehiro
S
Kondo
Shiro
S
D018926:Anti-Allergic Agents / Q000378:metabolism*; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism; D002478:Cells, Cultured; D002802:Cholinesterases / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism*; D004951:Esterification; D006801:Humans; D009297:Nasal Mucosa / Q000166:cytology; D011282:Pregnenediones / Q000378:metabolism*
D018926:Anti-Allergic Agents; D011282:Pregnenediones; C494355:desisobutyrylciclesonide; D002265:Carboxylic Ester Hydrolases; D002802:Cholinesterases; C120481:ciclesonide