Pharmacokinetic/pharmacodynamic modeling of cortisol suppression after oral administration of fluocortolone.

Fluocortolone is a potent corticosteroid used orally for the treatment of rheumatic diseases, asthma, and immunosuppression. A clinical study of nine healthy volunteers was conducted to determine the pharmacokinetics and cortisol suppression after administration of single oral doses of 20 mg, 50 mg, and 100 mg of fluocortolone. Blood samples were collected at 8:00 AM, 12:00 PM, and 4:00 PM on the day before treatment, and 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 28, 32, 48, 52, and 56 hours after administration of the drug. Concentrations of fluocortolone and cortisol were measured in plasma by a reversed phase high-performance liquid chromatography system. Cortisol suppression was chosen as the pharmacodynamic parameter. Total concentrations were converted into unbound concentrations using a two-protein, one-ligand equation. The unbound concentrations were fitted using a one-compartment body model equation with first-order absorption. A linear release-rate model was used to characterize the cortisol data. The data were fitted using a common E50 value of 0.95 +/- 0.22 ng/mL for the mean data. The value of E50 was in close agreement with the prediction based on relative glucocorticoid receptor affinity.

[The metabolism of hydrocortisone, prednisolone and fluocortolone (author's transl)]. / Ein Beitrag zum metabolismus von kortisol, prednisolon und fluocrotolon.

The plasma levels of hydrocortisone, prednisolone and fluocortolone were studied in healthy males by a competitive protein-binding technique after separation by thin-layer chromatography. Cortisone showed a mean morning level of 440 nmol/l +/- 165 nmol/l and a half life of 4.8 hours. The half life of prednisolone was determined after intravenous injection of 25 mg and found to be 2.4 hours and that of fluocortolone, after oral administration of 60 mg, was calculated to be 1.7 hours.

Pharmacokinetics of fluocortolone in man.

The kinetics of the synthetic corticoid fluocortolone was determined in 9 healthy female volunteers after a single oral dose of 20 mg. The maximal plasma level fluocortolone (Cmax) of 202 +/- 70 ng/ml occurred within 85 +/- 32 min of oral intake after which it declined monoexponentially. Total plasma clearance was 6.48 +/- 2.07 ml/min X kg and the clearance of unbound fluocortolone was 60.38 +/- 26.67 ml/min X kg. Plasma protein binding was 83 to 95%. The volume of distribution at steady-state was 1.01 +/- 0.341/kg for total fluocortolone and 11.21 +/- 3.771/kg for unbound drug. The results of the study characterize the kinetics of unbound fluocortolone for the first time. In addition, the kinetics of total fluocortolone presented here confirm values calculated previously.

Determination of trace levels of steroids in blood plasma by liquid chromatography with peroxyoxalate chemiluminescence detection.

A highly sensitive and specific liquid chromatographic procedure with peroxyoxalate chemiluminescence detection has been developed for the determination of fluocortin butyl, a 3 alpha-ketocorticosteroid, in blood plasma. The technique employs dansylation of the steroid to provide a highly chemiluminescent derivative. After separation by reversed-phase liquid chromatography, reagents necessary for chemiluminescence are added, followed by detection in a conventional fluorimetric detector in which the excitation source is deactivated. The precision is 2.5% relative standard deviation at the 10 ng/ml level, and the response is linear up to at least 4 ng injected steroid. The procedure requires only 1 ml blood plasma and has a limit of detection of 100 pg/ml or 7.5 pg injected steroid. The system is reliably used for routine pharmacokinetic studies and with modifications, is applicable to other steroids as well.

[Binding of cortisol, fluocortolone and difluocortolone to human plasma proteins (author's transl)]. / Bindung von cortisol, Fluocortolon und Difluocortolon an Humanplasmaproteine.

The binding properties of [3H]cortisol, [3H]fluocortolone and [3H]difluocortolone by human plasma, human albumin, human- beta- and gamma-globulins have been studied by equilibrium dialysis. Cortisol, in physiological concentrations (0,4 micromol/l), is 98% bound in human plasma at 25 degrees C, fluocortolone 96% and diflucortolone 85%. Uncer physiological conditions cortisol is mainly bound to the corticosteroid binding globulin (transcortin). 2/3 of fluocortolone is bound to transcortin and 1/3 to albumin and globulins, whereas difluocortolone is mainly bound to albumin and to globulins but not to transcortin. The binding affinities of beta- and gamma-globulins are -ery low for the corticoids investigated, but they are higher for fluocortolone and difluocortolone than for cortisol.

Fluocortolone: pharmacokinetics and effect on plasma cortisol level.

The pharmacokinetics of fluocortolone and its effect on plasma cortisol levels are described after oral administration of 20, 50 and 100 mg to 9 healthy adults. The concentrations of fluocortolone and cortisol in plasma were measured simultaneously by HPLC with UV detection. Fluocortolone was rapidly absorbed after all doses, giving the maximum plasma level after 1.4-2.1 h. After ingestion of 20, 50 and 100 mg, the peak levels were 199, 419 and 812 ng/ml, respectively. The maximum plasma levels and areas under the plasma level-time curves increased in proportion to the dose. Post-maximum plasma levels declined monoexponentially with a half-life of 1.76 h. Plasma half-life (t1/2 = 1.76 h), volume of distribution (1.03 l/kg) and oral clearance (6.9 ml/min/kg) were independent of the dose. The intensity and duration of adrenal suppression was dose dependent. Maximum suppression was observed 8 hours after fluocortolone. Clearcut suppression of cortisol levels after 24 hours was only seen following 100 mg fluocortolone.

The effect of short-and long-term corticosteroid treatment on sleep-associated growth hormone secretion.

Eight healthy medical studients and four renal transplant patients had blood sampled two or three times hourly throughout EEG monitored nocturnal sleep. This was carried out on the healthy subjects for a total of 12 nights without medication (control nights asleep), a total of 12 nights following 40 mg of flucortolone the previous morning, and a total of 6 nights with similar blood sampling when sleep was prevented (control nights awake). Four renal transplant patients who were receiving long-term therapy with prednisolone were similarly studied (total of 7 nights asleep). Circulating corticosteroid and growth hormone (GH) levels were determined. A peak of GH was seen during the first 2 h of sleep on the control nights when slow-wave sleep predominated. The GH peak was absent on the control nights awake. The pattern of plasma corticosteroid levels was identical during control nights asleep and awake. Both single-dose and chronic corticosteroid administration inhibited the GH peak associated with slow-wave sleep. Chronic corticosteroid therapy, but no single-dose administration in the morning, suppressed the circadian rise of plasma corticosteroids which normally occurs late in sleep.