[Pharmacology of inhaled corticosteroids: new data and therapeutic implications].
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Administration, Inhalation↗
Biomedical subjects
S Edsbäcker
Publications and source records attributed to S Edsbäcker.
Pharmacokinetics and systemic effects of inhaled fluticasone propionate in healthy subjects.
AIMS: The present study was undertaken to see whether the difference in plasma cortisol suppression between single and repeated dosing of fluticasone propionate (FP) can be explained by systemic accumulation. METHODS: Twelve healthy subjects (six women) were given, in a crossover fashion, a single dose inhalation (1000 micrograms) of FP via Diskhaler and repeated inhalations (1000 micrograms twice daily) every 12 h during 7 days. There was a washout period of 2 weeks between the treatments. An intravenous dose of 20 micrograms FP was given as a reference. Plasma concentrations of FP for each treatment were determined by liquid chromatography plus tandem mass spectrometry. Plasma cortisol after the inhaled doses was determined using an immunoassay and was compared with baseline values. RESULTS: The average plasma concentration of FP was about 1.7 times higher after multiple inhalations than after a single dose. Systemic availability, mainly attributable to pulmonary deposition, was 15.6 [13.6-18.0]% of the nominal dose. Daytime plasma cortisol suppression vs baseline was 47 [20-65]% and 95 [93-97]% for the single and repeated doses, respectivley. CONCLUSIONS: To conclude, a slow elimination of FP leads to accumulation during repeated dosing. This accumulation may explain the marked decrease in plasma cortisol seen during treatment with fluticasone propionate within the clinical dose range.
Administration, Inhalation↗
Lung deposition of budesonide from Turbuhaler is twice that from a pressurized metered-dose inhaler P-MDI.
The pulmonary and systemic availability of budesonide after inhalation from a dry powder inhaler, Turbuhaler, and from a pressurized metered-dose inhaler (P-MDI) were compared in healthy volunteers. Two different methods were used to assess pulmonary availability: 1) calculated from the systemic availability corrected for an oral availability of 13% (n = 24); and 2) after blocking of gastrointestinal absorption by administration of a charcoal suspension (n = 13). An intravenous infusion of budesonide was used as a reference. The systemic availability of budesonide, calculated as a geometric mean and expressed as percentage of the metered dose, was 38% for Turbuhaler and 26% for P-MDI. The pulmonary availability, calculated using the first method, was 32% and 15% for Turbuhaler and P-MDI, respectively; and, using the second method, 32% and 18%, respectively. The results of the present study indicate that administration of budesonide via Turbuhaler gives rise to a lung deposition which is approximately twice that of a P-MDI, with less variability, but that systemic availability is only increased by approximately 50%. Thus, the present data suggest that by administrating budesonide via Turbuhaler, instead of a P-MDI, the same degree of asthma control can be achieved with a lower dose, which, in turn, reduces the risk of undesired systemic effects.
Administration, Oral↗
Relationship between lung tissue and blood plasma concentrations of inhaled budesonide.
In 11 patients, in whom a lung lobe or whole lung was to be resected, a single dose of 1.6 mg inhaled budesonide was given pre-operatively. In 9 of them, concentrations of the drug in both lung tissue and blood plasma were measured. Budesonide concentrations in lung tissue, at least 90 min after dosage, were 2.1-8.9 nmol kg-1. Concentrations in blood plasma (0.27-1.1 nmol kg-1) were 1/8th of those in lung tissue.
Administration, Inhalation↗
Pharmacokinetics of budesonide enema in patients with distal ulcerative colitis or proctitis.
Pharmacokinetic data obtained after one dose of a 2-mg budesonide enema were compared with data obtained after the last dose of four weeks of daily treatment in 24 patients with active distal ulcerative colitis or proctitis. This open multicentre study involved 28 eligible patients. Sigmoidoscopy and biopsy scores improved significantly (P < 0.002) during the four-week treatment period. Maximal plasma concentration (Cmax) of budesonide was 2.1 nmol/L 1.3 h after the first dose and 2.5 nmol/L 1.2 h after the last dose; the difference was not significant. The area under the curve (AUC) of plasma concentration vs. time was after the first dose 9.7 nmol h/L and after the last dose 11.6 nmol h/L (P < 0.03). The small increase in AUC may be attributed to improved absorption. During the last dose interval, minimal plasma concentration was below the limit of quantitation in most subjects. The Cmax and AUC of budesonide increased slightly after four weeks of treatment, but budesonide did not accumulate. Mean morning plasma cortisol values did not change significantly during treatment (P = 0.083), although a small change in cortisol levels between the first visit (pre-treatment) and last visit was positively correlated to the Cmax of budesonide measured at the last visit (P = 0.012).
Administration, Topical↗
Oral availability of fluticasone propionate.
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Administration, Oral↗
The use of on-line liquid chromatography/mass spectrometry and stable isotope techniques for the identification of budesonide metabolites.
A moving belt interface was used to identify budesonide metabolites, obtained from rat and mouse liver incubations, by liquid chromatography/mass spectrometry (LC/MS). The metabolites were separated on a small-bore C18 column with an ethanol/water gradient as mobile phase at a flow rate of 0.2 ml min-1. A spray device was used for deposition of the aqueous solvent on to the belt. Chemical ionization mass spectra were obtained with methane as the reagent gas. Deuterium-labelled budesonide, which was used to facilitate metabolite identification by the isotope cluster technique, was found to be slightly separated from the unlabelled analogue on the LC column. Incubations were also performed under 18O2 to elucidate the mechanism of a new metabolic pathway (16 alpha, 17 alpha-acetal splitting) and to confirm the oxidative nature of reactions leading to hydroxylated metabolites. The moving belt LC/MS technique afforded higher sensitivity, and gave more abundant MH+ ions of the compounds studied, than previously found by direct probe mass spectrometry. Phthalate ester background, partly from the polymide belt, complicated the identification of minor metabolites.
Animals↗
Nasal bioavailability and systemic effects of the glucocorticoid budesonide in man.
Budesonide, a topically potent glucocorticoid, was administered to 4 healthy volunteers by i.v. infusion and by nasal instillation of 100 micrograms tritium-labelled drug. Plasma was analyzed by liquid chromatography plus scintillation counting of collected fractions. After i.v. administration the plasma clearance was 0.921/min and the apparent volume of distribution was 2.81/kg. After nasal administration, the time to reach the peak plasma level was approximately 30 min, and the systemic availability was 102%. Budesonide had marginal effects on plasma cortisol and white blood cell counts either after i.v. or nasal administration. Thus, nasally instilled budesonide in solution is rapidly and completely absorbed from the nasal mucosa. The systemic effects after this clinically recommended nasal dose were negligible.
Administration, Topical↗
Kinetics of the epimeric glucocorticoid budesonide.
Budesonide is a potent nonhalogenated glucocorticoid consisting of a 1/1 mixture of the two epimers 22R and 22S. The kinetics of these epimers were studied in six healthy male subjects after intravenous administration of 500 micrograms 3H-budesonide. Estimation of the epimer concentrations in plasma was made possible by development of an HPLC method for simultaneous separation and quantification. The plasma t 1/2, distribution volume (V beta), and plasma clearance for epimer 22R were (mean +/- SD) 2.66 +/- 0.57 hr, 425 +/- 100 l, and 117 +/- 40 l/hr. The corresponding values for epimer 22S were 2.71 +/- 0.69 hr, 245 +/- 38 l, and 67 +/- 19 l/hr. Differences in V beta and plasma clearance between the two were significant. The larger V beta noted for epimer 22R may be a result of higher tissue affinity. The high plasma clearance for both epimers should largely reflect their high rate of liver biotransformation.
Adult↗
In vitro biotransformation of glucocorticoids in liver and skin homogenate fraction from man, rat and hairless mouse.
The pharmacological effects of glucocorticoids are greatly influenced by their pharmacokinetic properties. In the present report, the in vitro biotransformation of the topical glucocorticoids [3H]-budesonide ([3H]-BUD). [3H]-triamcinolone acetonide ([3H]-TAAc) and [3H]-hydrocortisone ([3H]-HC) was studied in the 9000 g liver and skin supernatant from man, rat and hairless mouse. The rate of disappearance of the compounds was estimated during the initial 30 min of incubation by high performance liquid chromatography. In human liver the half life (t1/2) rank order was [3H]-BUD (7--23 min) less than [3H]-TAAc (13--68 min) less than [3H]-HC (40--67 min), in rat liver [3H]-HC (14--21 min) less than [3H]-BUD (28--38 min) less than [3H]-TAAc (161--196 min) and in hairless mouse liver [3H]-BUD (17--22 min) less than [3H]-TAAc (21--34 min) less than [3H]-HC (82--165 min). Negligible biotransformation of these glucocorticoids occurred in skin. BUD is a one to one mixture of the [22R]- and [22S]-epimers. It was found that the [22R]-epimer was more susceptible to liver biotransformation than the [22S]-epimer of [3H]-BUD. The results are discussed with particular reference to the extent of systemic side effects of these compounds.
Adolescent↗
Biotransformation rate (in vitro) and systemic potency (in vivo) of the topical glucocorticoid budesonide in male and female rats.
Budesonide is a glucocorticoid of clinical interest for the topical treatment of skin and respiratory diseases. The in vitro liver biotransformation rate and in vivo systemic potency (thymus involution) of budesonide were studied in male and female rats. The biotransformation rate of [3H]-budesonide was about 4 times slower in the female than in the male rat liver 9000 g supernatant (t 1/2; 230 and 57 min, respectively). The systemic potency of budesonide after peroral or subcutaneous administration was higher (by factors of 6 and 2, respectively) in the female than in the male rat. These results suggest that the liver biotransformation rate of budesonide is of great importance in reducing its systemic action in the male rat.
Animals↗
Pharmacokinetics and metabolism of budesonide, a selective glucocorticoid.
Budesonide is a highly potent non-halogenated glucocorticoid intended for the local treatment of lung disease. Budesonide is designed to have a high ratio between local and systemic effects. The biotransformation of 3H-budesonide was studied in vitro and compared to the biotransformation of 3H-triamcinolone acetonide and 3H-beclomethasone dipropionate. Budesonide was degraded 3--6 times as rapidly as triamcinolone acetonide in human and rat liver, respectively. Beclomethasone dipropionate was immediately hydrolyzed to the monopropionate in human liver. The degradation of beclomethasone monopropionate is the step that represents the major loss in biological activity and this step was only about one fourth as fast as the degradation of budesonide. 6 beta-hydroxy budesonide and 16 alpha-hydroxy prednisolone are two of the main metabolites of budesonide in human liver. The formation of these metabolites are important inactivation steps. The pharmacokinetics of 3H-budesonide was studied in healthy male volunteers after inhalation, oral and intravenous administration. The plasma half-life was 2.8 +/- 1.1 h (mean +/- SD), distribution volume 301.3 +/ 41.7 1 and plasma clearance 83.7 +/- 27.5 1/h. The systemic availability was 10.7 +/- 4.3% after oral administration and 72.8 +/- 42.0% after inhalation, corrected for the amounts of substance deposited in the inhalation device and oral cavity.
Animals↗
Liver metabolism of budesonide in rat, mouse, and man. Comparative aspects.
The metabolism of budesonide, (22RS)-16 alpha, 17 alpha-butylidenedioxy-11 beta,21-dihydroxypregna-1,4-diene- 3,20-dione, was studied in the 9000g supernatant fraction of livers from rat, mouse, and man. The two budesonide C-22 epimers produced different metabolites. This was explained by substrate-selective oxidation of the nonsymmetric 16 alpha, 17 alpha-acetal substituent. Epimer 22R gave 16 alpha-hydroxyprednisolone, while epimer 22S produced a metabolite tentatively identified as 23-hydroxybudesonide. Otherwise, budesonide followed the general metabolic pathways reported for synthetic glucocorticoids. Thus, oxidative metabolism predominated, 6 beta-hydroxybudesonide and delta 6-budesonide being identified in all investigated species. Reductive metabolism, giving 4,5 beta-dihydrobudesonide and 3,4,5 beta-tetrahydrobudesonide, was most pronounced in the rat. Rates and routes of budesonide metabolism were most similar in mouse and human livers. This implies that the mouse is a more relevant species than the rat in studies of the pharmacology and toxicology of budesonide.
Aged↗
Metabolic acetal splitting of budesonide. A novel inactivation pathway for topical glucocorticoids.
Topical glucocorticoids usually have a high intrinsic glucocorticoid potency and may, after systemic uptake, induce side effects. The systemic inactivation of budesonide is rapid due to extensive liver biotransformation. The major metabolic pathway, 16 alpha, 17 alpha-acetal splitting, is unique for budesonide within this group of compounds. This biotransformation is catalyzed by microsomal monooxygenases and proceeds via hydroxylation and subsequent rearrangement to an intermediary ester. The ester is cleaved by hydrolysis to 16 alpha-hydroxyprednisolone and butyric acid. The hydrolysis product 16 alpha-hydroxyprednisolone has strongly reduced glucocorticoid activity.
Acetals↗
Metabolic pathways of the topical glucocorticoid budesonide in man.
The metabolic pathways of budesonide[(22RS)-16 alpha, 17 alpha-butylidenedioxy-11 beta, 21-dihydroxypregna-1,4-diene-3,20-dione] in human liver 9000g supernatant fraction were studied. A comparison was made between the in vitro metabolite pattern and the metabolite pattern in plasma obtained after iv administration of tritiated budesonide to man. No qualitative difference could be found, which indicates that the in vitro model is useful to predict results in vivo. The two major metabolites formed in vitro were identified by HPLC and mass spectrometry as 6 beta-hydroxybudesonide and 16 alpha-hydroxyprednisolone. Loss of the acetal group was not observed when desonide (11 beta,21-dihydroxy-16 alpha,17 alpha-isopropylidenedioxy-pregna-1,4-diene-3,20-dione) was incubated with human liver 9000g supernatant fraction. Neither could 16 alpha-hydroxyprednisolone be detected after incubation of the (22S)-epimer of budesonide with the same medium. The cleavage of the acetal moiety is therefore suggested to be the result of a substrate-selective metabolic pathway.
Adolescent↗
Beclomethasone vs budesonide.
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Administration, Topical↗