<i>In vitro</i> metabolism of ciclesonide in human nasal epithelial cells

Sato, Hideyuki; Nave, Ruediger; Nonaka, Takashi; Mochizuki, Takashi; Takahama, Shigehiro; Kondô, Shirô

doi:10.1002/bdd.529

Cited by 22 publications

(21 citation statements)

References 22 publications

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“…Ciclesonide (CIC) is a novel, nonhalogenated ICS that has been developed to incorporate PK properties that lead to high efficacy and an improved safety profile [ 11 - 15 ]. The prodrug CIC is administered as an inactive parent compound to the lower airways, where it is converted to its pharmacologically active metabolite desisobutyryl-ciclesonide (des-CIC) by endogenous esterases [ 12 , 16 - 19 ] Des-CIC has a high affinity to the glucocorticoid receptor, comparable with beclomethasone-17-monopropionate (BMP), whereas BUD has a slightly lower and FP a higher binding affinity [ 11 ]. Within the lung cells, des-CIC and BUD undergo reversible esterification with fatty acids at the C-21 position of the molecules.…”

Section: Introductionmentioning

confidence: 99%

In vitro metabolism of beclomethasone dipropionate, budesonide, ciclesonide, and fluticasone propionate in human lung precision-cut tissue slices

Nave¹,

Fisher²,

McCracken³

2007

Respir Res

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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).

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Section: Introductionmentioning

confidence: 99%

In vitro metabolism of beclomethasone dipropionate, budesonide, ciclesonide, and fluticasone propionate in human lung precision-cut tissue slices

Nave¹,

Fisher²,

McCracken³

2007

Respir Res

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“…These findings indicate that the active metabolite is present for at least 24 hours in nasal epithelia and thus supports once daily administration. 15,16 Ciclesonide, when administered intranasally, shows negligible absorption into systemic circulation. In three separate studies conducted in patients as young as 2 years of age involving administration of ciclesonide nasal spray at doses up to 800 g/day, the majority of serum samples contained undetectable levels of ciclesonide and des-cic.…”

Section: Pharmacology Of Ciclesonidementioning

confidence: 99%

“…24 Preclinical studies conducted in rabbits have indicated that when ciclesonide is delivered as a hypotonic suspension to the nasal mucosa, there is enhanced uptake of ciclesonide, a higher intracellular concentration of the parent and active metabolite, and longer retention of the active metabolite compared with when ciclesonide is suspended and administered in an isotonic medium. 15,16 The intracellular concentrations of ciclesonide and des-cic administered in a hypotonic versus isotonic formulation are displayed in Fig. 3.…”

Section: Formulation Aspects Of Intranasal Ciclesonidementioning

confidence: 99%

Ciclesonide, a hypotonic intranasal corticosteroid

Neffen¹,

Wingertzahn²

2010

allergy asthma proc

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Intranasal corticosteroids (INCSs) are established as the first-line treatment of moderate to severe allergic rhinitis (AR) in both adults and children. Compared with other nasal allergy medications, INCSs are the most effective at providing symptom relief and increasing quality of life. Ciclesonide nasal spray is the most recently approved INCS. The formulation of ciclesonide does not contain benzylalkonium chloride or phenyl ethyl alcohol, excipients that have been associated with reduced mucociliary transport, and unpleasant sensory perceptions. Additionally, ciclesonide has been formulated in a hypotonic suspension that has been shown to optimize intranasal absorption and it has a lower volume of spray compared with most other INCS products. Systemic exposure to ciclesonide and its active metabolite desisobutyryl-ciclesonide is low after intranasal administration. High protein binding ( approximately 99%) and rapid first-pass clearance further reduce systemic exposure to the drug. Studies up to 1 year have shown that intranasal ciclesonide does not cause cortisol suppression as monotherapy and does not have an additive effect on the hypothalamic-pituitary-adrenal axis function when administered in combination with inhaled corticosteroids. The efficacy of ciclesonide, 200 microg/day, has been shown in pediatric, adolescent, and adult patients with moderate to severe seasonal AR and perennial AR treated for up to 1 year. Additionally, environmental exposure unit studies have established an onset of action as early as 1 hour after administration. Ciclesonide nasal spray has also been shown to have an acceptable safety profile in patients with AR as young as 2 years of age. Thus, intranasal ciclesonide appears to provide an additional effective treatment option for patients with AR.

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“…(Derived from data of Nave et al 2007; Nonaka et al 2007; Sato et al 2007a; Nonaka unpublished data).…”

Section: Figurementioning

confidence: 99%

Metabolism of ciclesonide in the upper and lower airways: review of available data

Nave¹,

McCracken²

2008

JAA

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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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In vitro metabolism of ciclesonide in human nasal epithelial cells

Cited by 22 publications

References 22 publications

In vitro metabolism of beclomethasone dipropionate, budesonide, ciclesonide, and fluticasone propionate in human lung precision-cut tissue slices

In vitro metabolism of beclomethasone dipropionate, budesonide, ciclesonide, and fluticasone propionate in human lung precision-cut tissue slices

Ciclesonide, a hypotonic intranasal corticosteroid

Metabolism of ciclesonide in the upper and lower airways: review of available data

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