Deposition and metabolism of inhaled ciclesonide in the human lung

Abstract

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.

Ciclesonide modulates in vitro allergen-driven activation of blood mononuclear cells and allergen-specific T-cell blasts

“…Taken together these in vitro results are in favor of the effective conversion of CIC into its active metabolite by human PBMCs and prove the ability of this pro-drug to downregulate the immune response toward allergens at concentrations similar to those obtained in vivo at bronchial level [35]. In the present study we did not evaluate the concentrations of ciclesonide and des-ciclesonide in cell culture supernatants.…”

Pharmacokinetic Mechanism Involved in the Prolonged High Retention of Laninamivir in Mouse Respiratory Tissues after Intranasal Administration of its Prodrug Laninamivir Octanoate

“…In addition to metabolic enzymes such as P450 enzymes and conjugation enzymes, esterase is currently known to be expressed in the respiratory tissues (Zhang et al, 2006;Somers et al, 2007) and engage in the hydrolysis/activation of several inhaled prodrugs, such as beclomethasone dipropionate (Becoride; GlaxoSmithKline plc) (Wörthwein and Rohdewald, 1990) and ciclesonide (Alvesco; Nycomed International Management GmbH, Zurich, Switzerland) (Nave et al, 2010). In the case of LO as well, hydrolysis in the respiratory tissues was observed both in vivo (Fig.…”

Emerging corticosteroid agonists for the treatment of asthma

“…First, ciclesonide is administered as an inactive pro-drug, which is not activated until reaching the site of action in the airways [48]. Here, it is cleaved by esterases to the active metabolite, which is then conjugated with fatty acids [49,50]. This conjugate has a high lipophilicity with high affinity for the GR, which may contribute to the long duration of action exhibited by ciclesonide.…”