Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
9017422 | Pulmonary Pharmacology & Therapeutics | 2005 | 7 Pages |
Abstract
Ciclesonide, an inhaled corticosteroid (ICS) with prolonged anti-inflammatory activity, is being developed for the treatment of asthma. Fatty acid conjugation of ICS is thought to be related to prolonged ICS activity. In vitro studies demonstrated that ciclesonide is converted to an active metabolite, desisobutyryl-ciclesonide (des-CIC), which undergoes reversible fatty acid conjugation. We tested the in vivo metabolism of ciclesonide in the lung by exposing rats to inhaled ciclesonide (0.16Â mg/kg/day) for 1Â h daily over 4 weeks. Lungs (n=6 per time point) were extracted with ethanol 2, 5, and â¼27Â h after the final treatment. Ciclesonide and des-CIC concentrations were determined using solid-phase extraction and reverse-phase high-performance liquid chromatography with tandem mass spectrometry (LC/MS/MS). Concentrations of fatty acid ester conjugates were indirectly assessed using enzymatic de-esterification before LC/MS/MS. At 2 and 5Â h, fatty acid conjugates of des-CIC were the major metabolites (61 and 55%, respectively). Ciclesonide, des-CIC, and fatty acid conjugates of des-CIC were clearly present in lung samples the day after the last inhalation. This in vivo study confirmed ciclesonide activation to des-CIC and formation of fatty acid conjugates. The presence of des-CIC fatty acid conjugates at >24Â h after dosing suggests that ciclesonide is appropriate for once-daily dosing.
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Authors
R. Nave, W. Meyer, R. Fuhst, K. Zech,