In vitro metabolism of beclomethasone dipropionate, budesonide, ciclesonide, and fluticasone propionate in human lung precision-cut tissue slices.
BACKGROUND
The therapeutic effect of inhaled corticosteroids (ICS) may be affected by the metabolism of the drug in the target organ. We investigated the in vitro metabolism of beclomethasone dipropionate (BDP), budesonide (BUD), ciclesonide (CIC), and fluticasone propionate (FP) in human lung precision-cut tissue slices. CIC, a new generation ICS, is hydrolyzed by esterases in the upper and lower airways to its pharmacologically active metabolite desisobutyryl-ciclesonide (des-CIC).


METHODS
Lung tissue slices were incubated with BDP, BUD, CIC, and FP (initial target concentration of 25 microM) for 2, 6, and 24 h. Cellular viability was assessed using adenosine 5'-triphosphate content and protein synthesis in lung slices. Metabolites and remaining parent compounds in the tissue samples were analyzed by HPLC with UV detection.


RESULTS
BDP was hydrolyzed to the pharmacologically active metabolite beclomethasone-17-monopropionate (BMP) and, predominantly, to inactive beclomethasone (BOH). CIC was hydrolyzed initially to des-CIC with a slower rate compared to BDP. A distinctly smaller amount (approximately 10-fold less) of fatty acid esters were formed by BMP (and/or BOH) than by BUD or des-CIC. The highest relative amounts of fatty acid esters were detected for BUD. For FP, no metabolites were detected at any time point. The amount of drug-related material in lung tissue (based on initial concentrations) at 24 h was highest for CIC, followed by BUD and FP; the smallest amount was detected for BDP.


CONCLUSIONS
The in vitro metabolic pathways of the tested ICS in human lung tissue were differing. While FP was metabolically stable, the majority of BDP was converted to inactive polar metabolites. The formation of fatty acid conjugates was confirmed for BMP (and/or BOH), BUD, and des-CIC.
Nave
Ruediger
R
DMPK, Nycomed GmbH, Konstanz, Germany. ruediger.nave@nycomed.com
Fisher
Robyn
R
McCracken
Nigel
N
D000328:Adult; D000730:Androstadienes / Q000378:metabolism; D018926:Anti-Allergic Agents / Q000378:metabolism*; D001507:Beclomethasone / Q000378:metabolism; D019819:Budesonide / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D000068298:Fluticasone; D005938:Glucocorticoids / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011282:Pregnenediones / Q000378:metabolism
D000730:Androstadienes; D018926:Anti-Allergic Agents; D005938:Glucocorticoids; D011282:Pregnenediones; D019819:Budesonide; D000068298:Fluticasone; D001507:Beclomethasone; C120481:ciclesonide