<i>In Vitro</i> metabolism of ciclesonide in human lung and liver precision‐cut tissue slices

Nave, Ruediger; Fisher, Ron; Zech, K.

doi:10.1002/bdd.500

Cited by 57 publications

(65 citation statements)

References 32 publications

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“…We have shown earlier in this system that only the intact BUD (and not BUD esters) is released from trachea into incubation medium (MillerLarsson et al, 1998). Similarly, only CIC and CIC-AM, but not CIC-AM esters, were detected in medium after incubation with human lung slices (Nave et al, 2006b).…”

Section: Resultsmentioning

confidence: 85%

“…CIC is inactive, but it is hydrolyzed to an active metabolite (CIC-AM) that was reported to form fatty acid esters in airway tissue. CIC-AM esters have been detected in vitro in human alveolar and nasal epithelial cells (Nave et al, 2005b(Nave et al, , 2006c and in rat and human lung slices (Nave et al, 2004(Nave et al, , 2006a. They were also detected after inhalation of CIC in rat and human lungs (Nave et al, 2005a;Watz et al, 2006).…”

mentioning

confidence: 99%

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Differences in Endogenous Esterification and Retention in the Rat Trachea between Budesonide and Ciclesonide Active Metabolite

Lexmuller

Gullstrand²,

Axelsson³

et al. 2007

Drug Metab Dispos

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ABSTRACT:The airway retention of inhaled glucocorticosteroids (GCs) depends largely on their lipophilicity. Inhaled budesonide (BUD) becomes highly lipophilic reversibly by the formation of esters acting as a reservoir of active BUD. Ciclesonide (CIC) was also reported to form esters after hydrolysis to active metabolite (CIC-AM). We have investigated lipophilicity and airway retention of BUD, CIC/ CIC-AM, fluticasone propionate (FP), and mometasone furoate (MF), and compared esterification of BUD and CIC-AM and its contribution to GC airway retention. Rat tracheas were preincubated with the esterification inhibitor cyclandelate or vehicle. A 3 H-GC (ϳ10 ؊7 M: BUD, CIC, CIC-AM, FP, MF) was added for 20 min.After incubation, one half of the trachea was used for analysis of GC uptake and the other to analyze GC release during 3 h in drug-free medium. GC species in trachea halves were analyzed by radiochromatography. At 20 min, the uptake of BUD was similar to that of CIC/CIC-AM; however, the BUD-ester pool was 9-fold greater (p < 0.01). BUD overall retention in trachea at 3 h was greater than that of other GCs (p < 0.01), and the BUD-ester pool was 3-fold greater than the CIC-AM-ester pool (p < 0.01). Cyclandelate decreased the initial BUD-and CIC-AM-ester pools (p < 0.01), and reduced the overall retention of BUD at 3 h (p < 0.01) but not of CIC-AM. Thus, BUD becomes esterified in the airways more promptly and to a greater extent than CIC-AM, and BUD esterification prolongs BUD airway retention. In contrast, airway retention of CIC-AM and CIC seems to be determined mainly by their lipophilicity, similar to FP and MF, which are not esterified.

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Section: Resultsmentioning

confidence: 85%

mentioning

confidence: 99%

Differences in Endogenous Esterification and Retention in the Rat Trachea between Budesonide and Ciclesonide Active Metabolite

Lexmuller

Gullstrand²,

Axelsson³

et al. 2007

Drug Metab Dispos

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“…[8,21,22] Ciclesonide fatty acid conjugates are five-fold more lipophilic than budesonide fatty acid conjugates. [7] Increased lipophilicity and the ability to form fatty acid conjugates may increase ciclesonide retention in the lung [7,8] and, thereby, may contribute to the clinical efficacy of once-daily ciclesonide observed in this study. In addition, the high pulmonary deposition of ciclesonide and the high affinity of the active metabolite for the glucocorticoid receptor potentially contribute to the improvements in lung function and asthma symptoms.…”

Section: Discussionmentioning

confidence: 99%

“…[6,7] Subsequently, des-CIC undergoes reversible esterification to form fatty acid conjugates in the lung that serve as a depot for the slow release of the active drug. [8] Finally, des-CIC is converted into a series of inactive metabolites that are eliminated from the body. [9] Several clinical studies have reported the efficacy and safety profiles of ciclesonide in patients with persistent asthma over a range of doses (80-640 µg).…”

Section: Introductionmentioning

confidence: 99%

Ciclesonide is more effective than budesonide in the treatment of persistent asthma

Ukena

Biberger²,

Steinijans³

et al. 2007

Pulmonary Pharmacology & Therapeutics

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Background: Ciclesonide is a lung-activated inhaled corticosteroid that provides effective control of persistent asthma. The objective of this study was to compare the efficacy and safety of once-daily ciclesonide versus once-daily budesonide in patients with asthma. Methods:A total of 399 patients with asthma were randomised to receive once-daily ciclesonide 320 µg ex-actuator (equivalent to 400 µg ex-valve) or once-daily budesonide 400 µg for 12 weeks. The primary endpoint was forced expiratory volume in 1 second (FEV 1 ). Additional efficacy variables included forced vital capacity (FVC), peak expiratory flow (PEF), asthma symptoms, use of rescue medication and time to onset of effect. Adverse events were monitored throughout the study. Conclusion:Once-daily ciclesonide was more effective than once-daily budesonide in improving FEV 1 , FVC and PEF. Ciclesonide also had an earlier onset of action than budesonide in patients with persistent asthma. Both ciclesonide and budesonide had good safety and tolerability profiles.

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“…In vitro studies in human tissue and in vivo studies in rats have reported that des-CIC forms reversible conjugates with fatty acids, which are pharmacologically inactive and do not bind to the glucocorticoid receptor [7,[13][14][15]. The findings regarding the metabolism of CIC derived from in vitro and animal studies have yet to be confirmed by in vivo studies in human subjects.…”

mentioning

confidence: 99%

Deposition and metabolism of inhaled ciclesonide in the human lung

Nave¹,

Watz²,

Hoffmann³

et al. 2010

Eur Respir J

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Ciclesonide is an inhaled corticosteroid, administered as a prodrug via a metereddose inhaler. Following deposition in the lung, ciclesonide is hydrolysed by esterases to form the pharmacologically active metabolite desisobutyryl-ciclesonide (des-CIC). Formation of des-CIC, as well as reversible esterification of des-CIC with fatty acids, has been demonstrated in vitro. The aim of this study was to investigate the in vivo metabolism of ciclesonide in the human lung.This single-dose, open-label, nonrandomised study was performed in 20 patients undergoing planned lung surgery for treatment of malignant pulmonary lesions. Patients inhaled a single dose of 1,280 mg ciclesonide at various time-points between 2 and 24 h prior to lung tissue resection. The concentration of ciclesonide, des-CIC and fatty acid conjugates of des-CIC in tissue samples was determined. Serum samples for pharmacokinetic analysis were taken at several time-points after inhalation.The pharmacokinetics in serum indicated that the inhalation by the patients was adequate. Metabolites (des-CIC, des-CIC oleate and des-CIC palmitate) were detected in the resected central and peripheral lung tissues. A substantial portion of ciclesonide was already activated to des-CIC at the first time-point of tissue analysis.Activation of ciclesonide and formation of des-CIC fatty acid conjugates was confirmed in vivo in the human lung.

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In Vitro metabolism of ciclesonide in human lung and liver precision‐cut tissue slices

Cited by 57 publications

References 32 publications

Differences in Endogenous Esterification and Retention in the Rat Trachea between Budesonide and Ciclesonide Active Metabolite

Differences in Endogenous Esterification and Retention in the Rat Trachea between Budesonide and Ciclesonide Active Metabolite

Ciclesonide is more effective than budesonide in the treatment of persistent asthma

Deposition and metabolism of inhaled ciclesonide in the human lung

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