Deposition and metabolism of inhaled ciclesonide in the human lung.
Ciclesonide is an inhaled corticosteroid, administered as a prodrug via a metered-dose inhaler. Following deposition in the lung, ciclesonide is hydrolysed by esterases to form the pharmacologically active metabolite desisobutyryl-ciclesonide (des-CIC). Formation of des-CIC, as well as reversible esterification of des-CIC with fatty acids, has been demonstrated in vitro. The aim of this study was to investigate the in vivo metabolism of ciclesonide in the human lung. This single-dose, open-label, nonrandomised study was performed in 20 patients undergoing planned lung surgery for treatment of malignant pulmonary lesions. Patients inhaled a single dose of 1,280 μg ciclesonide at various time-points between 2 and 24 h prior to lung tissue resection. The concentration of ciclesonide, des-CIC and fatty acid conjugates of des-CIC in tissue samples was determined. Serum samples for pharmacokinetic analysis were taken at several time-points after inhalation. The pharmacokinetics in serum indicated that the inhalation by the patients was adequate. Metabolites (des-CIC, des-CIC oleate and des-CIC palmitate) were detected in the resected central and peripheral lung tissues. A substantial portion of ciclesonide was already activated to des-CIC at the first time-point of tissue analysis. Activation of ciclesonide and formation of des-CIC fatty acid conjugates was confirmed in vivo in the human lung.
Nave
R
R
Dept of Pharmacometrics, Nycomed GmbH, Byk-Gulden-Str 2, 78467 Konstanz, Germany. ruediger.nave@nycomed.com
Watz
H
H
Hoffmann
H
H
Boss
H
H
Magnussen
H
H
D000280:Administration, Inhalation; D000293:Adolescent; D000328:Adult; D000368:Aged; D018926:Anti-Allergic Agents / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D006801:Humans; D008168:Lung / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D011282:Pregnenediones / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D014018:Tissue Distribution; D055815:Young Adult
D018926:Anti-Allergic Agents; D005227:Fatty Acids; D011282:Pregnenediones; C120481:ciclesonide