ABSTRACT
The pharmacokinetics (PK) and pharmacodynamics (effects on blood lymphocytes) of dexamethasone (D) after intravenous (i.v.) administration of dexamethasone phosphate (DP, 10 mg, equivalent to 8.3 mg of dexamethasone) and after intravenous and intramuscular (i.m.) administration of dexamethasone sulfobenzoate sodium (DS, 9.15 mg, equivalent to 6 mg of dexamethasone) were assessed. Only 25% of DS was converted into dexamethasone with a half-life for DS of 5.4 hours and 7.4 hours after i.v. and i.m. administration, respectively. Consequently, the mean residence time of D after both i.m. and i.v. administration of DS (10.4-11.6 h) was longer than that after DP administration (6.1 h). The smaller lymphocyte suppression induced by DS (50% of that after DP administration) was shown to be related to differences in the pharmacokinetics. This study revealed significant differences in the pharmacokinetics of D after administration of DS and DP and stresses the importance of the prodrug for the pharmacological response. Because of the slow and incomplete conversion of DS into dexamethasone, its use in emergency medicine situations should be critically evaluated.
Subject(s)
Dexamethasone/administration & dosage , Dexamethasone/pharmacokinetics , Lymphocytes/drug effects , Lymphopenia/chemically induced , Adult , Anti-Inflammatory Agents/therapeutic use , Cross-Over Studies , Dexamethasone/adverse effects , Dexamethasone/analogs & derivatives , Flow Cytometry , Glucocorticoids/therapeutic use , Half-Life , Humans , Injections, Intramuscular , Injections, Intravenous , Male , Metabolic Clearance Rate , Models, Biological , RadioimmunoassayABSTRACT
A combined HPLC/RIA procedure is described for the selective determination of budesonide (BUD) in plasma. The assay involves the extraction of plasma or serum samples with ethylacetate, consequent HPLC separation of intact budesonide from cross-reacting metabolites on a C8 reversed phase column, collection of the budesonide containing fraction and determination of budesonide immunoreactivity with the budesonide antiserum. The method was accurate, sensitive (IC50 value of 0.9 ng ml-1) and reproducible (intra- and inter-day less than 15%) with a limit of quantification of 0.133 ng ml-1 (RSD < 25%). The evaluation of a limited number of clinical samples after oral administration of budesonide by both the HPLC/RIA procedure and a direct RIA using the same antiserum differed in average by a factor of 2, with the ratio of HPLC/RIA-RIA results declining as a function of time. Thus, this ratio might be a suitable indicator for probing for the ratio of budesonide and overall metabolites on a semi-quantitative level.
Subject(s)
Anti-Inflammatory Agents/blood , Budesonide/blood , Chromatography, High Pressure Liquid/methods , Radioimmunoassay/methods , Administration, Oral , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/pharmacokinetics , Budesonide/administration & dosage , Budesonide/pharmacokinetics , Humans , Quality ControlABSTRACT
A combined high performance liquid chromatography/radioimmunoassay procedure is described for the simultaneous determination of dexamethasone (DEX) and its prodrug dexamethasone-21-sulphobenzoate sodium (DSS) in plasma. After precipitation of the plasma proteins by acetonitrile, the protein-free supernatant was injected onto a C18 reversed phase liquid chromatographic system and DSS- and DEX-containing fractions were collected. Hydrolysis of DSS by 0.01 N NaOH, followed by fractions extraction of both hydrolysed DSS and DEX fractions with ethyl acetate allowed the use of a dexamethasone-specific radioimmunoassay for the selective determination of both compounds. The method is accurate and reproducible (intraday variability for DSS and DEX < 6%, interday variability for DEX 14%), allowing quantification of DEX and DSS as low as 0.3 ng/mL and 0.7 ng/mL, respectively.
Subject(s)
Dexamethasone/analogs & derivatives , Dexamethasone/blood , Prodrugs/analysis , Chromatography, High Pressure Liquid , Humans , Hydrolysis , Radioimmunoassay , Spectrophotometry, UltravioletABSTRACT
A series of non-fluorinated glucocorticoids, cortienic acid analogs with a 17 beta-chloromethyl ester and various 17 alpha-ether functions, were tested for their affinity to the rat-lung type-II glucocorticoid receptor. The relative binding affinity of a set of 9 compounds was determined in a competitive experiment with [1,2,4-3H]triamcinolone acetonide. The highest binding affinities were observed with the 17 alpha-propoxy and butoxy analogs which were 1.3 times more active than the standard dexamethasone. Quantitative analysis of the results suggested that steric factors and lipophilicity of the side-chain were the major parameters affecting receptor affinity. Representative members of the series were compared to betamethasone 17 alpha-valerate in a vasonstriction test. The results paralleled those of the receptor binding experiment, indicating that the new steroids have good skin-permeation properties and good glucocorticoid activity.
