21-deacetyldeflazacort and deflazacort

Deflazacort (DFZ, a prodrug) is well absorbed and rapidly metabolized into the active metabolite 21-hydroxydeflazacort (21-OH DFZ) after oral administration. The aim of this study is to evaluate the pharmacokinetic properties of 21-OH DFZ in healthy Chinese volunteers after a single and multiple oral administration of DFZ tablets under fed condition. Twelve volunteers (six males and six females) were administered a single dose of 6 mg or 12 mg or 24 mg of DFZ in three different periods separately, according to the 3 x 3 Latin square design. Between each administration period there was a washout period of one week. The multiple-dose study of 12 mg dose DFZ per day for 7 consecutive days was started after a 1 w washout period when the single-dose study completed. The pharmacokinetic parameters of 21-OH DFZ after the single oral administration of 6 mg, 12 mg and 24 mg DFZ tablets were as follows: (37.7 +/- 11.6), (61.5 +/- 17.7) and (123 +/- 23) ng x mL(-1) for C(max); (1.90 +/- 0.32), (1.96 +/- 0.27) and (2.13 +/- 0.34) h for t1/2; (96.6 +/- 25.9), (190 +/- 44) and (422 +/- 107) ng x h x mL(-1) for AUC(0-14 h), respectively. After the multiple dose administration, the mean plasma concentration at steady-state C(av) was (7.00 +/- 1.66) ng x mL(-1) and the degree of plasma concentration fluctuation DF was 7.7 +/- 1.2. The results showed that the pharmacokinetic characteristics of 21-OH DFZ in healthy Chinese volunteers were linear over the dose range of 6 to 24 mg. No significant gender differences were found in the pharmacokinetics of 21-OH DFZ in healthy Chinese volunteers. After the multiple dose administration of 12 mg DFZ for 7 d, no accumulation of 21-OH DFZ in healthy Chinese volunteers was observed.

Topics: Administration, Oral; Area Under Curve; Asian People; Female; Healthy Volunteers; Humans; Male; Pregnenediones; Tablets

The acute effects of deflazacort (MDL 458, CAS 14484-47-0) and its metabolite, 21-desacetyl-deflazacort, on allergic reactions in animal models were investigated and compared with those of prednisolone. Deflazacort, 21-desacetyl-deflazacort and prednisolone all inhibited 48-h homologous passive cutaneous anaphylaxis in rats, but had no significant effects on active systemic anaphylaxis in mice, on the Schultz-Dale reaction in the isolated guinea-pig trachea or on compound 48/80-induced histamine release in rat peritoneal mast cells. All three agents inhibited reversed cutaneous anaphylaxis in rats and the Arthus reaction in mice. The inhibitory effects of deflazacort on the passive cutaneous anaphylaxis, the reversed cutaneous anaphylaxis and the Arthus reaction were similar to those of 21-desacetyl-deflazacort and were stronger than those of prednisolone. Delayed type hypersensitivity in mice was also inhibited by deflazacort and 21-desacetyl-deflazacort, but prednisolone, at the doses used in the present study, had little effect on this immune response. These findings indicate that while deflazacort and 21-desacetyl-deflazacort have stronger anti-allergic effects than prednisolone, they seem to have little acute effect on mast cell degranulation or on chemical mediators at the receptor site.

Topics: Anaphylaxis; Animals; Arthus Reaction; Guinea Pigs; Histamine Release; Hypersensitivity; Hypersensitivity, Delayed; Immunosuppressive Agents; In Vitro Techniques; Isometric Contraction; Male; Mast Cells; Mice; Mice, Inbred ICR; Muscle, Smooth; Passive Cutaneous Anaphylaxis; Prednisolone; Pregnenediones; Rats; Rats, Wistar

Two HPLC methods for the separation of a mixture of corticoids including the oxazolinic corticoid deflazacort and its metabolite 21-hydroxydeflazacort using different water-tetrahydrofuran mobile phases were developed. Both separations allowed the detection and determination of fifteen out of sixteen corticoids using different C18 columns. Extraction data for deflazacort and its metabolite using different extraction procedures are also reported. These separation conditions were applied to urine samples from two male volunteers administered Dezacor, with both doping control and clinical purposes.

Topics: Adrenal Cortex Hormones; Adult; Anti-Inflammatory Agents; Chromatography, High Pressure Liquid; Cortisone; Furans; Humans; Hydrocortisone; Male; Molecular Structure; Pregnenediones; Quality Control; Sensitivity and Specificity; Spectrophotometry, Ultraviolet; Water

The in vitro immunosuppressive effect of deflazacort, a new bone-sparing glucocorticoid, and its biologically active metabolite, 21-deacetyl-deflazacort, was examined on phytohaemagglutinin (PHA) stimulated human peripheral blood lymphocytes (PBL) as well as on natural killer (NK) and killer (K) cell activity. Deflazacort and the 21-deacetyl metabolite were as potent as prednisolone and hydrocortisone in suppressing PHA stimulated lymphocytes in a dose dependent way, but all were less potent than methylprednisolone. The physiological metabolites of hydrocortisone, dihydrocortisol and tetrahydrocortisol were without any immunosuppressive effects in vitro. Deflazacort, 21-deacetyl-deflazacort, and methylprednisolone suppressed NK cell activity, while hydrocortisone and aldosterone had no effect on NK cells. K cell activity was resistent to all tested glucocorticoids except methylprednisolone at high concentrations. The present results indicate that deflazacort and 21-deacetyl-deflazacort are potent immunosuppressive drugs in vitro and, on a molar basis, equally as potent as prednisolone.

Topics: Aldosterone; Anti-Inflammatory Agents; Antibody-Dependent Cell Cytotoxicity; Humans; Hydrocortisone; Immunosuppressive Agents; Killer Cells, Natural; Lymphocyte Activation; Methylprednisolone; Pregnenediones; T-Lymphocytes

Male Sprague-Dawley rats were injected with 1 mg/100 g bw/day of prednisone, 1.25 mg/1--g bw/day of deflazacort, or its metabolite, for a period of 20 days. Epiphyseal cartilage slices were incubated in a modified Krebs Ringer bicarbonate buffer, at 37 degrees C for 60 min, with either 14C-1- or 14C-6-glucose to quantitate both the absolute and relative rates of pentose shunt versus aerobic and anaerobic glycolytic activity, respectively. Measurements of both total and radioactive glucose uptake, lactate production and 14CO2 generation were expressed as either mumoles or DPM/mg cellular DNA/hr, respectively. This study demonstrated: (1) chronic prednisone administration decreased anaerobic glycolysis (glucose uptake and lactate production) 3-fold (P less than 0.01); (2) prednisone on a chronic basis produced no measured alteration in either the pentose shunt or Kreb's cycle activity; (3) both deflazacort and the deflazacort metabolite significantly stimulated (P less than 0.02) anaerobic glycolytic activity in epiphyseal cartilage tissue. In contrast to prednisone, the administration of either deflazacort or its L-6485 metabolite did not inhibit the glycolytic pathway of metabolism so necessary for epiphyseal cartilage growth and mineralization.

Topics: Aerobiosis; Anaerobiosis; Animals; Cartilage, Articular; Epiphyses; Glucose; Glycolysis; In Vitro Techniques; Lactates; Male; Pentose Phosphate Pathway; Prednisone; Pregnenediones; Rats; Rats, Inbred Strains