Research article

Ciclesonide uptake and metabolism in human alveolar type II epithelial cells (A549)

Takashi Nonaka¹ , Rüdiger Nave² , Nigel McCracken² , Atsuko Kawashimo¹ and Yasuhiro Katsuura¹

¹Teijin Institute for Biomedical Research, Teijin Pharma Limited, 4-3-2 Asahigaoka, Hino, Tokyo 191-8512, Japan

²Nycomed GmbH, Byk-Gulden-Str. 2, 78467 Konstanz, Germany

author email corresponding author email

BMC Pharmacology 2007, 7:12doi:10.1186/1471-2210-7-12

Published:	27 September 2007

Abstract

Background

Ciclesonide is a novel inhaled corticosteroid for the treatment of airway inflammation. In this study we investigated uptake and in vitro metabolism of ciclesonide in human alveolar type II epithelial cells (A549). Ciclesonide uptake was compared with fluticasone propionate, an inhaled corticosteroid that is not metabolized in lung tissue. A549 cells were incubated with 2 × 10^-8 M ciclesonide or fluticasone propionate for 3 to 30 min to determine uptake; or with 2 × 10^-8 M ciclesonide for 1 h, followed by incubation with drug-free buffer for 3, 6, and 24 h to analyze in vitro metabolism. High performance liquid chromatography with tandem mass spectrometry was used to measure the concentrations of both corticosteroids and metabolites.

Results

At all time points the mean intracellular concentration was higher for ciclesonide when compared with fluticasone propionate. Activation of ciclesonide to desisobutyryl-ciclesonide (des-CIC) was confirmed and conjugates of des-CIC with fatty acids were detected. The intracellular concentration of ciclesonide decreased over time, whereas the concentration of des-CIC remained relatively stable: 2.27 to 3.19 pmol/dish between 3 and 24 h. The concentration of des-CIC fatty acid conjugates increased over time, with des-CIC-oleate being the main metabolite.

Conclusion

Uptake of ciclesonide into A549 cells was more efficient than that of the less lipophilic fluticasone propionate. Intracellular concentrations of the pharmacologically active metabolite des-CIC were maintained for up to 24 h. The local anti-inflammatory activity of ciclesonide in the lung may be prolonged by the slow release of active drug from the depot of fatty acid esters.