Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.1.8 (cholinesterase)
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Ciclesonide, a corticosteroid in development for allergic rhinitis, is converted to the pharmacologically active metabolite, desisobutyryl-ciclesonide (des-CIC), and des-CIC is subsequently esterified with fatty acids. Various experiments were performed to investigate ciclesonide metabolism in human nasal epithelial cells (HNEC). Human nasal epithelial cells were incubated with (a) 0.1 microM ciclesonide for 1 h and medium without ciclesonide for up to 24 h, (b) esterase inhibitors for 0.5 h followed by 5 microM ciclesonide for 6 h, or (c) 1 microM des-CIC for 6 h followed by medium without des-CIC for up to 24 h. Ciclesonide, des-CIC and des-CIC fatty acid conjugate concentrations were determined by high-performance liquid chromatography with tandem mass spectrometry. The amount of ciclesonide in HNEC decreased approximately 93-fold from 0.5 to 24 h. In contrast, des-CIC was present at constant levels throughout the post-treatment period. Furthermore, fatty acid conjugates of des-CIC were retained in HNEC up to 24 h post-treatment. Carboxylesterase and cholinesterase inhibitors decreased ciclesonide metabolism > or =50%. The total amounts of des-CIC fatty acid conjugates decreased and the extracellular amounts of des-CIC increased with time. In conclusion, ciclesonide was rapidly converted to des-CIC by carboxylesterases and cholinesterases, and des-CIC underwent reversible fatty acid conjugation in HNEC.
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PMID:In vitro metabolism of ciclesonide in human nasal epithelial cells. 1711 54

Ciclesonide (CIC) is an inhaled glucocorticosteroid. This study aimed to identify esterases involved in the metabolism of CIC to the active metabolite desisobutyryl-ciclesonide (des-CIC), and to measure hydrolysis rates in human liver, lung and plasma and normal human bronchial epithelial (NHBE) cells in vitro. Ciclesonide (5 microM and 500 microM) was incubated with microsomal or cytosolic fractions from liver, lung and plasma (n=4 for each) and des-CIC formation was determined by reverse-phase high-performance liquid chromatography with U.V. detection. The roles of carboxylesterase, cholinesterase and A-esterase in CIC hydrolysis were determined using a range of inhibitors. Inhibitor concentrations for liver and NHBE cells were 100 microM and 5 microM, respectively. Liver tissue had a higher activity for 500 microM CIC hydrolysis (microsomes: 25.4; cytosol: 62.9 nmol/g tissue/min) than peripheral lung (microsomes: 0.089; cytosol: 0.915 nmol/g tissue/min) or plasma (0.001 nmol/mL plasma/min), corresponding with high levels of carboxylesterase and cholinesterase in the liver compared with the lung. CIC (5 microM) was rapidly hydrolyzed by NHBE cells (approximately 30% conversion at 4h), with almost complete conversion by 24h. In liver and NHBE cells, major involvement of cytosolic carboxylesterases, with some contribution by cholinesterases, was indicated. The highest level of conversion was found in the liver, the site of inactivation of des-CIC through rapid oxidation by cytochrome P450. Carboxylesterases in bronchial epithelial cells probably contribute significantly to the conversion to des-CIC in the target organ, whereas low systemic levels of des-CIC are a result of the high metabolic clearance by the liver following CIC inhalation.
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PMID:The role of esterases in the metabolism of ciclesonide to desisobutyryl-ciclesonide in human tissue. 1733 75

Ciclesonide is a novel corticosteroid (CS) for the treatment of asthma and allergic rhinitis. After administration, the parent compound ciclesonide is converted by intracellular airway esterases to its pharmacologically active metabolite desisobutyryl-ciclesonide (des-CIC). We investigated the in vitro activation of ciclesonide and further esterification of des-CIC to (mainly) des-CIC oleate in several human target organ test systems. Human precision-cut lung slices, alveolar type II epithelial cells (A549), normal bronchial epithelial cells (NHBE), and nasal epithelial cells (HNEC) were incubated with ciclesonide. Enzymes characterization and the determination of the reversibility of fatty acid esterification was investigated in HNEC and NHBE. Ciclesonide was taken up and converted to des-CIC in all cellular test systems. Intracellular concentrations of des-CIC were maintained for up to 24 h. Formation of des-CIC oleate increased over time in HNEC, A549 cells, and lung slices. The formed des-CIC fatty acid conjugates were reconverted to des-CIC. Increasing concentrations of carboxylesterase and cholinesterase inhibitors progressively reduced the formation of metabolites. The results derived from these studies demonstrate the activation of ciclesonide to des-CIC in the upper and lower airways. The reversible formation of des-CIC fatty acid conjugates may prolong the anti-inflammatory activity of des-CIC and may allow for once-daily dosing.
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PMID:Metabolism of ciclesonide in the upper and lower airways: review of available data. 2143 81