Beclomethasone 17-monopropionate Research Articles

Beclomethasone dipropionate-loaded colon-targeting UniORV® for effective treatment of colitis

This study was undertaken to develop novel colon-targeting UniORV® (cUO) of beclomethasone dipropionate (BDP) for strategic oral delivery to the disease site of colitis. BDP-loaded cUO (cUO/BDP) was characterized regarding morphology and dissolution behaviors. Plasma levels of beclomethasone 17-monopropionate (17-BMP), a metabolite of BDP, were measured after oral administration of BDP samples to rats. Anti-inflammatory effects of oral BDP samples (50 μg-BDP/kg) were assessed in a rat model of colitis. The cUO/BDP was found to be a 300 μm-sized spherical particle. Compared with crystalline BDP, cUO/BDP exhibited a marked improvement in dissolution behavior only under colonic conditions, and the dissolution of BDP from cUO was negligible under upper gastrointestinal conditions. Oral BDP solution (5 mg-BDP/kg) led to a rapid increase in the plasma 17-BMP level with a maximum plasma concentration (Cmax) as high as 620 ng/mL and time to Cmax of 0.9 h. In contrast, Cmax of oral cUO/BDP was below 5 ng/mL, suggesting suppressed upper gastrointestinal absorption and enhanced delivery to the colon. In the rat model of colitis, compared with BDP solution, oral cUO/BDP significantly attenuated neutrophilia in the colon. The use of cUO may be a promising strategy to enhance the efficacy of BDP against colitis.

Ethnic Sensitivity Study of the Extrafine, Single-Inhaler, Triple Therapy Beclomethasone Dipropionate, Formoterol Fumarate, and Glycopyrronium Bromide Pressurized Metered Dose Inhaler in Japanese and Caucasian Healthy Individuals: A Randomized, Double-Blind, Single-Dose Crossover Study

PurposeA number of single-inhaler, fixed-dose, triple combinations are available for the management of chronic obstructive pulmonary disease and/or asthma. One of these is the extrafine formulation beclomethasone dipropionate, formoterol fumarate, glycopyrronium bromide (BDP/FF/GB). Given that differences in ethnicity can result in differences in systemic exposure, we evaluated the relative pharmacokinetic (PK) profiles of BDP/FF/GB in Japanese vs Caucasian healthy volunteers to assess the need for dose adjustment. MethodsThis randomized, double-blind, single-dose, 4-way crossover study recruited healthy men and women 20 to 55 years of age; for each Japanese person a Caucasian was enrolled who matched in terms of sex, age, and weight. Study treatments included BDP/FF/GB 200/12/25 and 400/12/25 μg (therapeutic), 800/48/100 μg (supratherapeutic), and placebo. PK blood samples were taken up to 24 hours for evaluation of BDP, beclomethasone 17-monopropionate (B17MP, an active metabolite of BDP), and formoterol and up to 48 h for GB. The primary objective was to characterize the PK profiles of BDP, FF, and GB after administration of a single dose of BDP/FF/GB in Caucasian and Japanese healthy volunteers in terms of the AUC0–t and Cmax of B17MP, formoterol, and GB. FindingsOf the 32 recruited participants (16 Japanese and 16 Caucasian ), 30 completed the study. A clear plasma exposure dose-response relationship was found for all 4 molecules. B17MP Cmax geometric mean ratios for Japanese vs Caucasian participants for the 3 study treatments ranged from 1.17 to 1.26, and AUC0–t ratios ranged from 1.16 to 1.22; thus, the findings were comparable between the ethnicities. Formoterol exposure was higher in Japanese than Caucasian participants (Cmax, 1.22–1.53; AUC0–t, 1.23–1.40). The GB Cmax with BDP/FF/GB 400/12/25 μg (1.09) and AUC0–t values for all three doses (0.98–1.17) were comparable in the 2 populations, but Cmax with 200/12/25 and 800/48/100 μg were higher in Japanese participants (1.32 and 1.42, respectively). Pharmacodynamic (cortisol, potassium, glucose, blood pressure, heart rate, and QT interval with the Fridericia correction) and safety profile results were similar in the 2 ethnicities, with most patients not experiencing any adverse events. ImplicationsExposure to BDP/FF/GB pressurized metered dose inhaler at therapeutic and supratherapeutic doses was associated with higher plasma levels in Japanese versus Caucasian healthy volunteers. These PK differences did not translate into meaningful differences in the safety or pharmacodynamic parameters assessed in this study and were consistent with the results of other long-term (52-week) published studies. Dose adjustments in Japanese people are not deemed necessary. ClinicalTrials.gov identifierNCT03859414.

Semi-mechanistic PK/PD model to assess pulmonary targeting of beclomethasone dipropionate and its active metabolite

PurposeThe objective of this study was to describe the pulmonary targeting of beclomethasone dipropionate (BDP) and its active metabolite beclomethasone 17-monopropionate (BMP) in rats using a semi-mechanistic PK/PD model. MethodsRat plasma and tissue concentrations of BDP and BMP, and tissue receptor occupancies of BMP after systemic and pulmonary delivery of BDP and BMP were integrated in a newly developed semi-mechanistic PK/PD model. ResultsAfter IV administration of BDP, 95.4% of BDP was converted to BMP, while after pulmonary delivery of BDP, 46.6% of deposited BDP was absorbed as BMP. The developed semi-mechanistic PK model described plasma and tissue concentrations of BDP and BMP as well as receptor occupancies sufficiently well. The model incorporated dissolution, metabolic activation, and drug absorption processes to describe the local fate of BDP and BMP after systemic and pulmonary delivery. Dissolution rate constants of BDP and BMP were estimated to be 0.47/h and 2.01/h, respectively, and the permeabilities in central lung were estimated to be 15.0 and 2.9 × 106 cm/s for BDP and BMP, respectively. The EC50 of the binding of BMP to to the receptor was estimated to be 0.0017 ng/ml. Overall, receptor occupancies in the lung were more pronounced than those in the systemic circulation after pulmonary delivery of BDP or BMP. Simulations using the developed semi-mechanistic PK/PD model demonstrated that a slow dissolution rate and low permeability can improve pulmonary targeting. ConclusionsA semi-mechanistic model was developed to describe the fate of an inhaled glucocorticoid pro-drug and its active metabolite in lung and the systemic circulation, both after pulmonary and systemic administration , thereby facilitating the understanding of the complex interplay between drug, prodrug and pharmacodynamic properties for quantifying the degree pulmonary targeting.

ETHNIC SENSITIVITY STUDY OF THE EXTRA-FINE SINGLE-INHALER TRIPLE THERAPY BECLOMETHASONE DIPROPIONATE/FORMOTEROL FUMARATE/GLYCOPYRRONIUM BROMIDE (BDP/FF/GB) PRESSURISED METERED DOSE INHALER (PMDI) IN HEALTHY JAPANESE AND CAUCASIAN SUBJECTS

SESSION TITLE: Pharmacotherapeutics Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: The prevalence of asthma in Japan has been increasing and a substantial proportion of patients continue to suffer from uncontrolled asthma. BDP/FF/GB pMDI is a single-inhaler ICS/LABA/LAMA triple therapy developed for the maintenance treatment of patients with asthma not adequately controlled on medium-to-high doses ICS/LABA. Since responses to pharmacological therapy can be affected by race and ethnicity, we investigated the pharmacokinetics (PK) and pharmacodynamics (PD) of BDP/FF/GB pMDI in healthy Japanese subjects in comparison to their Caucasian counterparts. METHODS: In this single-centre, randomised, double-blind, single dose, 4-way cross-over, placebo-controlled ethnic sensitivity study, healthy Japanese and Caucasian subjects received two different therapeutic doses (TD) of BDP/FF/GB, namely TD1 (200/12/25 µg) and TD2 (400/12/25 µg) and a supratherapeutic dose (STD, 800/48/100 µg), as well as a matching placebo separated by 21-day washout periods. Serial PK and PD assessments were conducted pre-dose and up to 48 hours post-dose. Vital signs, electrocardiograms (ECG) and treatment-emergent adverse events (TEAEs) were also monitored for the assessment of safety. Ethnic comparability was assessed by descriptive statistics. RESULTS: Thirty-two subjects (16 Japanese and 16 Caucasian subjects) were allocated to one of the 4 treatment sequences and thirty (93.8%) of the treated subjects completed the study. For B17MP (beclomethasone 17-monopropionate, the most active metabolite of BDP), Cmax and AUC0-t were generally comparable between Japanese and Caucasian subjects after all treatments, with geometric mean ratios from 1.17 to 1.26 (Cmax) and 1.16 to 1.22 (AUC0-t). For formoterol, Cmax and AUC0-t were higher in Japanese than in Caucasian subjects after all treatments with geometric mean ratios from 1.22 to 1.53 (Cmax) and from 1.23 to 1.40 (AUC0-t). For GB, Cmax was higher in Japanese than in Caucasian subjects after all treatments with geometric mean ratios from 1.09 to 1.42. The AUC0-t of GB was generally comparable between Japanese and Caucasian subjects after all treatments with geometric mean ratios from 0.98 to 1.17. In general, no clinically relevant differences were observed between Japanese and Caucasian subjects in PD and safety assessments. CONCLUSIONS: Exposure to extra-fine BDP/FF/GB pMDI was associated with comparable B17MP PK parameters whilst slight elevation in some PK parameters were observed for formoterol and GB in Japanese compared to Caucasian subjects. These results are in line with available literature on exposure to these drugs in Japanese subjects. CLINICAL IMPLICATIONS: No dose adjustments in Japanese are deemed necessary for BDP/FF/GB pMDI. DISCLOSURES: Employee relationship with Chiesi Farmaceutici SpA Please note: >$100000 Added 03/23/2020 by Massimo Cella, source=Web Response, value=Salary Employee relationship with Chiesi Farmaceutici S.p.A. Please note: >$100000 Added 03/21/2020 by Irisz Delestre-Levai, source=Web Response, value=Salary Employee relationship with Chiesi Farmaceutici, S.p.A. Please note: >$100000 Added 03/20/2020 by George Georges, source=Web Response, value=Salary No relevant relationships by Jorg Taubel, source=Web Response Employee relationship with Chiesi Please note: $1001 - $5000 Added 03/23/2020 by Anne Tulard, source=Web Response, value=Salary No relevant relationships by ANDREA VELE, source=Web Response

Microbial biotransformation of beclomethasone dipropionate by Aspergillus niger

In the present research, the steroidal anti-asthmatic drug beclomethasone dipropionate was subjected to microbial biotransformation by Aspergillus niger. Beclomethasone dipropionate was transformed into various metabolites first time from microbial transformation. New drug metabolites produced can act as new potential drug molecules and can replace the old drugs in terms of safety, efficacy, and least resistance. They were purified by preparative thin layer chromatography technique, and their structures were elucidated using modern spectroscopic techniques, such as 13C NMR, 1H NMR, HMQC, HMQC, COSY, and NOESY, and mass spectrometry, such as EI-MS. Four metabolites were purified: (i) beclomethasone 17-monopropionate, (ii) beclomethasone 21-monopropionate, (iii) beclomethasone, and (iv) 9beta,11beta-epoxy-17,21-dihydroxy-16beta-methylpregna-1,4-diene-3,20-dione 21-propionate.

Regulation of CYP3A genes by glucocorticoids in human lung cells

Inhaled glucocorticoids are the first-line treatment for patients with persistent asthma. However, approximately thirty percent of patients exhibit glucocorticoid insensitivity, which may involve excess metabolic clearance of the glucocorticoids by CYP3A enzymes in the lung. CYP3A4, 3A5, and 3A7 enzymes metabolize glucocorticoids, which in turn induce CYP3A genes. However, the mechanism of CYP3A5 mRNA regulation by glucocorticoids in lung cells has not been determined. In hepatocytes, glucocorticoids bind to the glucocorticoid receptor (GR), which induces the expression of the constitutive androstane receptor or pregnane X receptor; both of which bind to the retinoid X receptor alpha, leading to the induction of CYP3A4, 3A5, and 3A7. There is also evidence to suggest a direct induction of CYP3A5 by GR activation in liver cells. In this study, these pathways were evaluated as the mechanism for CYP3A5 mRNA induction by glucocorticoids in freshly isolated primary tracheal epithelial, adenocarcinomic human alveolar basal epithelial (A549), immortalized bronchial epithelial (BEAS-2B), primary normal human bronchial/tracheal epithelial (NHBE), primary small airway epithelial (SAEC), and primary lobar epithelial lung cells. In A549 cells, beclomethasone 17-monopropionate ([M1]) induced CYP3A5 mRNA through the glucocorticoid receptor. CYP3A5 mRNA induction by five different glucocorticoids was attenuated by inhibiting the glucocorticoid receptor using ketoconazole, and for beclomethasone dipropionate, using siRNA-mediated knock-down of the glucocorticoid receptor. The constitutive androstane receptor was not expressed in lung cells. SAEC cells, a primary lung cell line, expressed CYP3A5, but CYP3A5 mRNA was not induced by glucocorticoid treatment despite evaluating a multitude of cell culture conditions. None of the other lung cells expressed CYP3A4, 3A5 or 3A7 mRNA. These studies demonstrate that CYP3A5 mRNA is induced by glucocorticoids in A549 cells via the glucocorticoid receptor, but that additional undefined regulatory processes exist in primary lung cells.

Regulation of CYP3A genes by glucocorticoids in human lung cells

Inhaled glucocorticoids are the first-line treatment for patients with persistent asthma. However, approximately thirty percent of patients exhibit glucocorticoid insensitivity, which may involve excess metabolic clearance of the glucocorticoids by CYP3A enzymes in the lung. CYP3A4, 3A5, and 3A7 enzymes metabolize glucocorticoids, which in turn induce CYP3A genes. However, the mechanism of CYP3A5 mRNA regulation by glucocorticoids in lung cells has not been determined. In hepatocytes, glucocorticoids bind to the glucocorticoid receptor (GR), which induces the expression of the constitutive androstane receptor or pregnane X receptor; both of which bind to the retinoid X receptor alpha, leading to the induction of CYP3A4, 3A5, and 3A7. There is also evidence to suggest a direct induction of CYP3A5 by GR activation in liver cells. In this study, these pathways were evaluated as the mechanism for CYP3A5 mRNA induction by glucocorticoids in freshly isolated primary tracheal epithelial, adenocarcinomic human alveolar basal epithelial (A549), immortalized bronchial epithelial (BEAS-2B), primary normal human bronchial/tracheal epithelial (NHBE), primary small airway epithelial (SAEC), and primary lobar epithelial lung cells. In A549 cells, beclomethasone 17-monopropionate ([M1]) induced CYP3A5 mRNA through the glucocorticoid receptor. CYP3A5 mRNA induction by five different glucocorticoids was attenuated by inhibiting the glucocorticoid receptor using ketoconazole, and for beclomethasone dipropionate, using siRNA-mediated knock-down of the glucocorticoid receptor. The constitutive androstane receptor was not expressed in lung cells. SAEC cells, a primary lung cell line, expressed CYP3A5, but CYP3A5 mRNA was not induced by glucocorticoid treatment despite evaluating a multitude of cell culture conditions. None of the other lung cells expressed CYP3A4, 3A5 or 3A7 mRNA. These studies demonstrate that CYP3A5 mRNA is induced by glucocorticoids in A549 cells via the glucocorticoid receptor, but that additional undefined regulatory processes exist in primary lung cells.

Influence of low-dose ritonavir with and without darunavir on the pharmacokinetics and pharmacodynamics of inhaled beclomethasone.

To identify an alternative inhaled corticosteroid to fluticasone propionate that can be safely coadministered with HIV protease inhibitors, the safety and pharmacokinetics of beclomethasone dipropionate (BDP) and its active metabolite, beclomethasone 17-monopropionate (17-BMP), in combination with ritonavir (RTV) and darunavir/ritonavir (DRV/r) were assessed. Open-label, prospective, randomized pharmacokinetic and pharmacodynamic study in healthy volunteers. Thirty healthy volunteers received inhaled 160 μg bid BDP for 14 days and were then randomized (1:1:1) into 3 groups: group 1 (control) remained on BDP alone for 28 days, group 2 received 100 mg bid BDP + RTV for 28 days, and group 3 received 600/100 mg bid BDP + DRV/r for 28 days. Pharmacokinetic sampling for 17-BMP was performed on days 14 and 28, and pharmacokinetic parameter values were compared within patients and between groups. Cortisol stimulation testing was also performed on days 1, 14, 28, and 42 and compared within and between groups. Geometric mean ratios (day 28:day 14) (90% confidence interval) for 17-BMP area under the concentration-time curve in groups 1, 2, and 3, respectively, were 0.93 (0.81 to 1.06, P = 0.27), 2.08 (1.52 to 2.65, P = 0.006), and 0.89 (0.68 to 1.09, P = 0.61). There were no significant reductions in serum cortisol levels within or between groups (P > 0.05). DRV/r did not increase 17-BMP exposure, whereas RTV alone produced a statistically significant but clinically inconsequential 2-fold increase in 17-BMP exposure. Adrenal suppression was not observed in any of the study groups. These data suggest that BDP can be safely coadministered with DRV/r and likely other RTV-boosted protease inhibitors.

Rapid nongenomic actions of inhaled corticosteroids on long-acting β 2-agonist transport in the airway

Corticosteroids inhibit organic cation transporters (OCTs) that play an important role in drug absorption, tissue distribution and elimination. Corticosteroid sensitivity of bronchodilator trafficking in the airway tissue, however, is poorly understood. To assess the effects of inhaled corticosteroids on airway absorption and disposal mechanisms of long-acting β 2-agonists, human airway epithelial and smooth muscle cell uptake of tritiated formoterol and salmeterol was measured in vitro. Corticosteroids caused a rapid, concentration-dependent inhibition of uptake of the cationic formoterol by airway smooth muscle cells, but not airway epithelial cells. Uptake of the non-charged lipophilic salmeterol was corticosteroid-insensitive in both cell types. In smooth muscle cells, inhaled corticosteroids inhibited formoterol uptake with a novel potency rank order: des-ciclesonide > budesonide > beclomethasone 17-monopropionate > beclomethasone dipropionate > ciclesonide > fluticasone. The inhibitory action was rapidly reversible, and was not enhanced by prolonged corticosteroid exposure or sensitive to a transcription inhibitor. Suppression of OCT3 expression using lentivirus-mediated production of shRNA reduced corticosteroid sensitivity of formoterol uptake by smooth muscle cells. Our data support a corticosteroid insensitive absorption and a corticosteroid-sensitive disposition mechanism for cationic long-acting β 2-agonist bronchodilators in the airway. Potency rank order and other ‘classical’ features of anti-inflammatory effects do not apply to inhaled corticosteroids’ rapid drug transport actions.

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

BackgroundThe 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).MethodsLung tissue slices were incubated with BDP, BUD, CIC, and FP (initial target concentration of 25 μM) for 2, 6, and 24 h. Cellular viability was assessed using adenosine 5'-triphosphate content and protein synthesis in lung slices. Metabolites and remaining parent compounds in the tissue samples were analyzed by HPLC with UV detection.ResultsBDP was hydrolyzed to the pharmacologically active metabolite beclomethasone-17-monopropionate (BMP) and, predominantly, to inactive beclomethasone (BOH). CIC was hydrolyzed initially to des-CIC with a slower rate compared to BDP. A distinctly smaller amount (approximately 10-fold less) of fatty acid esters were formed by BMP (and/or BOH) than by BUD or des-CIC. The highest relative amounts of fatty acid esters were detected for BUD. For FP, no metabolites were detected at any time point. The amount of drug-related material in lung tissue (based on initial concentrations) at 24 h was highest for CIC, followed by BUD and FP; the smallest amount was detected for BDP.ConclusionThe in vitro metabolic pathways of the tested ICS in human lung tissue were differing. While FP was metabolically stable, the majority of BDP was converted to inactive polar metabolites. The formation of fatty acid conjugates was confirmed for BMP (and/or BOH), BUD, and des-CIC.

Pharmacokinetics of Beclomethasone Dipropionate in an Hydrofluoroalkane-134a Propellant System in Japanese Children with Bronchial Asthma

Hydrofluoroalkane-134a (HFA) has been shown to be a safe replacement for chlorofluorocarbons (CFCs) as a pharmaceutical propellant, with the advantage that it has no ozone-depleting potential. This is the first report of the pharmacokinetics of beclomethasone dipropionate (BDP) delivered from a pressurized solution formulation using an HFA propellant system (HFA-BDP) in Japanese children with bronchial asthma. Plasma concentrations of beclomethasone 17-monopropionate (17-BMP),a major metabolite of BDP, following an inhaled dose of HFA-BDP (200 microg as four inhalations from 50 microg/actuation) in five Japanese children with bronchial asthma were quantified and analyzed by a non-compartmental analysis to obtain pharmacokinetic parameters. The area under the concentration-time curve from time zero to the last quantifiable time (AUC(0-t)) was 1659 +/- 850 pg x h/mL (arithmetic mean +/- standard deviation (SD)), the maximum concentration observed (C(max)) was 825 +/- 453 pg/mL and the apparent elimination half-life (t(1/2)) was 2.1 +/- 0.7 hours. The time to reach Cmax Tmax was 0.5 hours in all patients. No special relationship was observed between these parameters and age or body weight. These parameters were compared with the previously reported parameters of American children with bronchial asthma. The Japanese/American ratio of the geometric means of each parameter was 1.36 for AUC(0-t), 1.04 for Cmax and 1.4 for t(1/2). The median of Tmax was 0.5 hours in American patients as well as Japanese patients. The pharmacokinetics of HFA-BDP in Japanese children with bronchial asthma are reported for the first time and a similarity to those in American children is suggested.

Simultaneous quantification of beclomethasone dipropionate and its metabolite, beclomethasone 17-monopropionate in rat and human plasma and different rat tissues by liquid chromatography–positive electrospray ionization tandem mass spectrometry

A sensitive, rapid and selective liquid chromatography–positive electrospray ionization tandem mass spectrometry (LC–(ESI+)-MS–MS) method has been developed and validated for the simultaneous quantification of beclomethasone dipropionate (BDP) and its active metabolite, beclomethasone 17-monopropionate (17-BMP) in rat plasma and different tissues using fluticasone propionate (FP) as the internal standard. The method was validated over a linear range from 0.05 to 5 ng/ml for both analytes. A solid-phase extraction procedure was used for plasma samples and a liquid–liquid extraction procedure for tissues samples (lung, liver and kidney). The between-day and within-day coefficients of variation for all compounds were ≤20% at the concentrations of lower limit of quantification (LLOQ) and ≤15% at other quality control concentrations. The same method was also partially validated for human plasma. The utility of this assay was demonstrated by monitoring BDP and 17-BMP plasma and tissue concentrations in an animal study designed for evaluation of pulmonary targeting after intratracheal administration of BDP dry powder.

Inhibition of interleukin‐5 mediated eosinophil viability by fluticasone 17‐propionate: comparison with other glucocorticoids

Inhaled glucocorticoids are commonly employed to treat patients with asthma. Eosinophils are important effector cells in the pathogenesis of asthma, and, in vitro, glucocorticoids modulate eosinophil viability. Using this glucocorticoid inhibition of eosinophil viability, we compared the in vitro potencies of several inhaled glucocorticoids with particular attention to fluticasone 17-propionate. Eosinophils from normal or mildly atopic donors were purified, cultured with cytokines and glucocorticoids, and on day 4, after staining with propidium iodide, analysed by flow cytometry. Eosinophil viability was prolonged by interleukin (IL)-5 in a concentration-dependent manner; in contrast, dexamethasone inhibited the IL-5 effect. Fluticasone 17-propionate, 1.0-1000 nM, also inhibited the IL-5 effect in a concentration-dependent manner; interestingly, at 0.1 nM fluticasone 17-propionate modestly, but significantly, enhanced eosinophil survival. High concentrations of IL-5 and granulocyte-macrophage colony-stimulating factor essentially completely overcame the inhibitory effect of 1000 nM fluticasone 17-propionate on eosinophil survival. In contrast, although interferon-gamma-mediated eosinophil viability was inhibited by 1.0-1000 nM fluticasone 17-propionate, this inhibition was not overcome by increased concentrations of interferon-gamma. Comparison of the glucocorticoid inhibition of eosinophil viability in the presence of 10 pg/mL IL-5 resulted in these drug IC50 values (in nM): fluticasone 17-propionate, 1.3; budesonide, 8.5; triamcinolone acetonide, 25; flunisolide, 32; dexamethasone, 94; beclomethasone 17-monopropionate, 210; beclomethasone 17,21-dipropionate, 290; and hydrocortisone, >1000. Fluticasone 17-propionate's effect on cytokine-mediated eosinophil viability is similar qualitatively to other glucocorticoid preparations. However, quantitatively, fluticasone 17-propionate has the most potent suppressive effects on IL-5 mediated eosinophil viability among the currently available inhaled glucocorticoids in the United States.

Relationship between the covalent binding of N-acetoxy-2-acetylaminofluorene to DNA and a steroidal esterase activity in human mononuclear leukocytes

A method for the quantitative assessment of steroidal esterase activity in viable human mononuclear leukocytes (HML) has been developed. It is based on estimating the conversion of [ 3H]beclomethasone-17,21-dipropionate (BDP) to beclomethasone-17-monopropionate (BMP) using TLC on silica gel 60 F-254 plates developed in a solvent system of chloroform/methanol (97:3, v/v). The cell assay procedure was dependent on BDP concentration, incubation time and cell concentration. The steroidal esterase activity was competed for by N-acetoxy- N-acetyl-2-aminofluorene (NA-AAF) and completely inhibited by 100 μM paraoxon. When [ 3H]NA-AAF binding to DNA was used as an indicator of HML esterase (deacylase) activity, BDP functioned as a substrate inhibitor. Parallel estimations of BDP metabolism and NA-AAF binding to DNA indicated striking correlations in the interindividual variations ( r = 0.62, P < 0.001) and in relation to the menstrual cycle events of a healthy female. Hence, these data indicate that both BDP and NA-AAF are metabolized by the same non-specific steroidal esterase present in HML.