| pA2 online © Copyright 2004 The British Pharmacological Society |
132P
University of Newcastle Winter Meeting December 2004 |
Esterases involved in the hydrolysis of ciclesonide *Elaine Mutch, **Karl Zech, **Ruediger Nave and *Faith M. Williams, *Environmental Medicine, The Medical School and IRES, University of Newcastle, UK. and **ALTANA Pharma A.G., Konstanz, Germany. |
|
Print abstractCiclesonide (CIC) is a novel inhaled glucocorticosteroid for the treatment of asthma. CIC is hydrolysed to the pharmacologically active metabolite desisobutyryl-ciclesonide (des-CIC) . The aim was to measure the hydrolysis of CIC by human tissues in vitro and normal human bronchial epithelial (NHBE) cells in culture.
The rates of hydrolysis of CIC (5µM) to des-CIC by microsomal or cytosolic fractions from human liver and lung and plasma were compared to NHBE cells in culture. The roles of carboxylesterase, cholinesterase, A-esterases and arylesterase in the hydrolysis of CIC were determined using the inhibitors, paraoxon, bis(p-nitrophenyl) phosphate, tetraisopropyl pyrophosphoramide (isoOMPA), eserine, EDTA and p-hydroxymercuribenzoate.
Human lung had very low activity (microsomes 0.09±0.20 and cytosol 0.92±0.05 nmol/g tissue/min) compared to human liver (25.4±4.7 and 62.9±11.4 nmol/g tissue/min, respectively) and there was little activity in plasma. CIC was rapidly hydrolysed by NHBE cells with 30% conversion at 4 h and complete conversion by 24 h. The concentration of des-CIC in the cells was much higher than the surrounding medium at all time points. In the liver and NHBE cells, the inhibition profile indicated major involvement of high affinity cytosolic carboxylesterases with some contribution from cholinesterases.
These studies confirmed that CIC is rapidly hydrolysed to des-CIC and that this is a major pathway of metabolism. Following an inhaled dose, carboxylesterases present in bronchial epithelial cells will greatly contribute to the activation of CIC.