Author(s): Mutch E, Nave R, McCracken N, Zech K, Williams FM
Abstract: Objective: Ciclesonide (CIC) is a novel inhaled glucocorticosteroid under development for the treatment of asthma. This study was conducted to identify esterases involved in the metabolism of CIC to the active metabolite desisobutyryl-ciclesonide (des-CIC) and to measure rates of hydrolysis of CIC in human liver, lung, and plasma and in normal human bronchial epithelial (NHBE) cells in vitro. Methods: To determine hydrolysis of CIC to des-CIC, CIC (5 µM and 500 µM) was incubated with microsomal or cytosolic fractions from liver (n = 4) and lung (n = 4) and plasma (n = 4). Desisobutyryl-ciclesonide formation from CIC was determined by reverse-phase high-pressure liquid chromatography at 242 nm. The roles of carboxylesterase, cholinesterase, and A-esterase in the hydrolysis of CIC by liver microsomal and cytosolic fractions and NHBE cells were determined using inhibitors p-hydroxymercuribenzoate, eserine, tetraisopropyl pyrophosphoramide, bis(p-nitrophenyl)phosphate, paraoxon, and ethylenediaminetetraacetic acid. Inhibitor concentrations for liver and NHBE cells were 100 µM and 5 µM, respectively. Results: Peripheral lung had low activity for the hydrolysis of 500 µM CIC (microsomes: 0.089 ± 0.18; cytosol: 0.915 ± 0.05 nmol/g tissue/min) compared with liver (microsomes: 25.4 ± 4.7; cytosol: 62.9 ± 11.4 nmol/g tissue/min). There was little hydrolysis in plasma. Ciclesonide was rapidly hydrolyzed by NHBE cells with approximately 30% conversion to des-CIC at 4 hours and nearly complete conversion by 24 hours. In liver and NHBE cells, the inhibition profile indicated major involvement of cytosolic carboxylesterases with some contribution by cholinesterases. Conclusion: These results suggest rapid activation of CIC to des-CIC by bronchial epithelial cells in culture, although there was little metabolism in human peripheral lung. Carboxylesterases present in bronchial epithelial cells probably contribute significantly to the activation of CIC to des-CIC.
Notes: This research was carried out in collaboration with Drs Zech and Nave (Altana Pharma AG, Germany)who invited us to investigate the esterase-mediated activation of ciclesonide in human tissues.