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

Figures & data

Figure 1 Intracellular activation of ciclesonide and reversible esterification of des-CIC. Reprinted from Nave R, Meyer W, Fuhst R, et al 2005b. Formation of fatty acid conjugates of ciclesonide active metabolite in the rat lung after 4-week inhalation of ciclesonide. Pulm Pharmacol Ther, 18:390–6. Copyright © Elsevier.

Abbreviations: GCS, glucocorticosteroid; des-CIC, desisobutyryl-ciclesonide.

Table 1 Uptake of ciclesonide into A549 cells (derived from data of Nonaka et al 2007)

Incubation time (min)	Mean concentration (pmol/dish)	Standard deviation
3	15.51	2.62
5	18.19	2.34
10	37.32	23.51
20	35.31	9.09
30	50.33	5.12

Notes: Intracellular concentrations of total ciclesonide (sum of ciclesonide, desisobutyryl-ciclesonide [des-CIC], and des-CIC fatty acid esters) in A549 cells during incubation with 2 × 10⁻⁸ M ciclesonide (5 dishes per time point).

Table 2 Inhibition of esterases in HNEC and HNBE cells (derived from data of Mutch et al 2007; Sato et al 2007a)

Inhibitor	Target esterase	Mean ± SEM % control activity
		HNEC	NHBE
Paraoxon	CarbE, BChE, AChE	25.0 ± 0.3	16.7 ± 0.7
BNPP	CarbE	24.9 ± 0.3	20.0 ± 3.8
Iso-OMPA	CarbE	29.3 ± 0.6	22.3 ± 3.8
Eserine	AChE	48.2 ± 0.3	28.7 ± 3.7
PMB	ArE	103.8 ± 0.8	90.3 ± 17.3
EDTA	A-E	105.8 ± 0.3	78.7 ± 4.7

Notes: data are expressed as percentage inhibition of control (no inhibitior) after incubation of cells with ciclesonide (5 × 10⁻⁶ mol/L) and esterase inhibitors (1 × 10⁻⁶ mol/L) (mean of duplicate estimations).

Abbreviations: HNEC, human bronchial epithelial cells; NHBE, normal human bronchial epithelial; CarbE, carboxylesterase; BChE, cholinesterase; AChE, acetylcholinesterase; ArE, arylesterase; A-E, A-esterase; BNPP, bis (p-nitrophenyl) phosphate; iso-OMPA, tetraisopropyl pyrophosphoramide; PMB, p-hydroxymercuribenzoate; EDTA, ethylenediaminetetraacetic acid.

Table 3 Formation of des-CIC fatty acid esters in airway epithelial cells and lung tissue

Test system	Substrate concentration (mol/L)	Substrate incubation time (h)	Sample collection time (h)	Mean (SD) intracellular concentrationa
				CIC	Des-CIC	Des-CIC-oleate	Des-CIC-palmitate
HNEC	1 × 10^−7	1 h	24 hb	0.31 (0.07)	5.39 (0.99)	48.43 (7.46)	1.87 (0.34)
NHBE cells	1 × 10^−6	1 h	24 hb	5.22 (2.53)	20.05 (1.55)	14.10 (1.38)	0.59 (0.19)
A549 cells	2 × 10^−8	1 h	24 hb	2.31(0.55)	3.19 (0.38)	23.20(6.03)	0.74 (0.15)
Lung slices	1 × 10^−5	24 h	24 h	2.93 (0.46)	3.23 (0.42)	3.46 (2.29)

a Amount of ciclesonide and metabolite in HNEC (pmol/dish), NHBE (pmol/well), A549 (pmol/dish), lung tissue (nmol).

b Incubation in substrate-free medium.

Abbreviations: HNEC, human bronchial epithelial cells; NHBE, normal human bronchial epithelial; des-CIC, desisobutyryl-ciclesonide. (Derived from data of Nave et al 2007; Nonaka et al 2007; Sato et al 2007a; Nonaka unpublished data).

Figure 2 Reversible conjugation of des-CIC with fatty acid in human bronchial epithelial cells. Data were represented as the mean ± SD from 6 wells. Time point of 0 h indicates the end of incubation with des-CIC for 6 h. Results at 0 h represent only the amount in the cells and results at 3, 6, and 24 h represent the sum of analyte in the cells and medium harvested (Nonaka unpublished data).

Abbreviations: des-CIC, desisobutyryl-ciclesonide; des-CIC FA conjugates, sum of des-CIC-oleate and des-CIC-palmitate.

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