Ulrich Täuber

Comparison of Serum Ethinyl Estradiol, Sex-Hormone-Binding Globulin, Corticoid-Binding Globulin and Cortisol Levels in Women Using Two Low-Dose Combined Oral Contraceptives

The study included 69 women taking a desogestrel (n = 30)- or gestodene (n = 39)-containing low-dose combined oral contraceptive for at least 3 months. Group size was calculated to detect a difference in mean values of 80% of 1 standard deviation (alpha = 0.05, beta = 0.1). Seven serum samples were obtained up to 4 h, and 1 sample 24 h, after drug intake on 1 day between the 10th and the 21st day of the cycle. The concentrations of sex-hormone-binding globulin (SHBG), corticoid-binding globulin (CBG) and cortisol were measured in a 0- to 4-hour serum pool by radioimmunoassay. Ethinyl estradiol (EE2) levels were analyzed in single and pooled samples using anti-EE2-6 beta-carboxymethyloxime-bovine serum albumin antiserum. The area under the curves (AUC) up to 4 and 24 h and Cmax and tmax were evaluated. Statistical analysis (analysis of covariance) did not reveal a dependence of values on duration of treatment or day of cycle. Both treatments resulted in almost identical values for all parameters evaluated. The mean levels of SHBG, CBG and cortisol were in the range of 186-226 nmol/l, 89-93 mg/l and 280-281 micrograms/l, respectively. Mean maximum EE2 levels of 106-129 pg/ml were found 1.6-1.8 h after pill intake and AUC0-4 h accounted for 329-374 pg.h.ml-1. The recently reported differences in serum EE2 and CBG levels between two groups of 11 women each treated with desogestrel- and gestodene-containing pills, respectively, could not be confirmed.

Single dose phakmacokinetics of gestodene in women after intravenous and oral administration

Abstract Six healthy female volunteers (age 25 – 39 years) received 75 μg gestodene intravenously followed by 3 oral administrations of 25, 75 and 125 μg gestodene together with 30 μg ethinylestradiol (EE 2 ) in a cross-over design. Gestodene plasma levels were determined using a specific RIA. After intravenous administration, plasma gestodene concentrations decayed triphasically with mean half-lives of 0.16 h, 1.5 h and 10 hours. The area under the plasma level curve, the total plasma clearance and the volume of distribution (V z ) were as follows: AUC = 35 ± 15 ng · h / ml , CL = 0.80 ± 0.53 ml / min / kg , and V z = 0.66 ± 0.43 1/ kg , respectively. After oral administration of all doses, maximum plasma levels of 1.0 (25 μg), 3.8 (75 μg) and 7.0 ng/ml (125 μg) were achieved between 1.4 and 1.9 hours after the intake. Post-maximum levels showed 2 disposition phases with half-lives of 1 and 12 – 14 hours. Absolute bioavailabilities were calculated as 87.5 ± 17.5 % (25 μg), 99.3 ± 10.9 % (75 μg ) and 110.8 ± 17.7 % (125 μg) indicating that gestodene is completely absorbed and systemically available at all doses investigated.

DEVELOPMENT AND APPLICATION OF A RADIOIMMUNOASSAY OF THE NEW PROGESTAGEN GESTODENE

A radioimmunoassay for the determination of gestodene (17-ethinyl-13-ethyl-17 beta-hydroxy-4,15-gonadien-3-one) in human plasma is described with regard to procedure, specificity, accuracy and reproducibility. Antiserum was raised against gestodene-3-O-(carboxymethyl)oxime-BSA in rabbits and [9,11-3H]-gestodene tracer was used with a specific radioactivity of 2.16 TBq/mmol. The final antiserum dilution was 1: 200,000. RIA was performed according to routine methods using diethylether plasma extracts and the charcoal separation technique. Cross-reactivity of antiserum with cortisol, 17 beta-estradiol, progesterone, testosterone and ethinylestradiol was less than 0.03%; levonorgestrel exhibited a 5% cross-reactivity. No cross-reactivity with metabolites of gestodene or ethinylestradiol was found. Accuracy and precision of the assay were tested using human plasma samples spiked with 1, 5 and 10 ng/ml gestodene. Accuracy was within 94 to 104% of the nominal values. Within-assay and between-assay coefficients of variation were in the range of 4.7-6.5% and 10.3-13.1%, resp. This RIA was used to follow plasma gestodene levels after single oral administration of 75 micrograms of gestodene combined with 30 micrograms ethinylestradiol as tablet and coated tablet in a cross-over design in 6 female test subjects. Plasma gestodene levels were equivalent after both treatments.

Prodrugs of Gestodene for Matrix-Type Transdermal Drug Delivery Systems

AbstractPurpose. The aim of this study was to enhance the transdermal absorption of the highly active progestin gestodene from matrix type transdermal delivery systems (TDDS) by formation of prodrugs with improved matrix solubility. Methods. Gestodene esters were synthesized via acylation of the drug with the respective carboxylic anhydrides. Subsequently TDDS were produced using the solvent cast method. Selected formulations were examined with in vitro diffusion experiments using skin of nude mice. Results. One prodrug, gestodene caproate proved to be an oil at ambient temperature and showed a very high solubilty of over 10.5% in the TDDS matrix. Within in vitro penetration studies using those systems the prodrug exhibited a significantly higher transdermal penetration rate than gestodene from reference systems. Furthermore, the prodrug was hydrolyzed to the parent drug to a high extent during the passage of the skin. Conclusions. Designing prodrugs to the requirements of matrix TDDS is an efficient way of enhancing the transdermal drug flux rate.

Protein binding of active ingredients and comparison of serum ethinyl estradiol sex hormone-binding globulin, corticosteroid-binding globulin, and cortisol levels in women using a combination of gestodene/ ethinyl estradiol (Femovan) or a combination of desogestrel/ ethinyl estradiol (Marvelon) and single-dose ethinyl estradiol bioequivalence from both oral contraceptives

Results from two clinical pharmacokinetic studies are given. The first study was an observational study in oral contraceptive users who took either a combination of gestodene and ethinyl estradiol (pill A, Femovan) or desogestrel and ethinyl estradiol (pill B, Marvelon). A total of 69 women (39 receiving pill A and 30 receiving pill B) were evaluated to determine serum ethinyl estradiol, sex hormone-binding globulin, corticosteroid-binding globulin, and cortisol levels. Samples were obtained on 1 day during the tenth to twenty-first days of pill intake. All women received the respective oral contraceptive for at least 3 months. The test power was such that an 80% difference of 1 standard deviation of each target variable would have been detected (alpha = 0.05; beta = 0.1). No statistically significant differences were found in sex hormone-binding globulin, corticosteroid-binding globulin, or cortisol serum levels between both groups. Time and height of maximum ethinyl estradiol levels were identical as was the area under the curves. Ex vivo protein-binding analysis of the progestins revealed a free portion of 0.6% for gestodene and 2.5% for 3-ketodesogestrel as the active metabolite of desogestrel. Sex hormone-binding globulin-bound portions were much higher for gestodene (75.3% +/- 9.1%) than for 3-ketodesogestrel (31.6% +/- 12%). The remaining fractions were bound to albumin. In a second study, ethinyl estradiol-bioequivalence from pills A and B was investigated in 18 women in a controlled, single-dose, randomized, crossover design. The area under the ethinyl estradiol serum levels were identical up to 4 hours after pill intake between both treatments. According to the relatively low variation in data in this group of women, a 10% difference in ethinyl estradiol-availability could have been detected. Both studies indicate that the pharmacokinetics of ethinyl estradiol were independent of the concomitantly administered progestin, that is, desogestel and gestodene.

Pharmacokinetics of gestodene and ethinyl estradiol after oral administration of a monophasic contraceptive.

The pharmacokinetic and protein-binding properties of gestodene and ethinyl estradiol have been investigated after single and multiple dosing in several studies in 83 healthy, young women. After oral administration, gestodene is completely absorbed and bioavailable and exhibits dose-linear pharmacokinetics. During long-term pill use, serum levels of gestodene were four to five times higher than after single administration, showing a periodic increase from day 1 to day 10 during each cycle. Ultrafiltration studies revealed that 75.3% of total serum gestodene is bound to sex hormone-binding globulin, 24.1% is bound to albumin, and only 0.6% is not protein bound. Thus gestodene levels during steady state are explained by an increase in sex hormone binding-globulin as a result of concomitant administered ethinyl estradiol and a specific binding of gestodene to this protein. Serum levels of ethinyl estradiol during single and multiple administration were identical and were not different from those observed with another preparation containing 30 micrograms of ethinyl estradiol.

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.

Pharmacokinetics of Antimycotics with Emphasis on Local Treatment

Antimycotics in current therapeutic use or in clinical development belong to the chemical classes listed in TABLE 1. The liveliest developments have been going on in the group of azoles. Approximately 10 azoles are already on the market, and at least the same number are in the clinical trial stage. In recent years, the allylamines with their extremely high efficacy against dermatophytes have attracted considerable interest. The antimycotics can be classified according to their route of administration and their therapeutic use as substances for systemic and local treatment. Substances for systemic treatment can be subdivided into those suited for treatment of systemic mycoses (such as amphotericin B and flucytosine), those suited for treatment of skin mycoses (such as griseofulvin and terbinafin), those suited for treatment of both systemic and superficial mycoses (such as ketoconazole), and those showing promise for the future (such as itraconazole and fluconazole). Substances for local treatment can be discriminated into those for treatment of superficial mycoses of the skin and vagina and those for treatment of mycoses of the gastrointestinal tract. Substances that are used systemically (intravenously or orally) are often also active after local application, but the converse is not necessarily true. The potential usefulness of an antimycotic for systemic and/or local application is not only determined by its antifungal activity (that is, its intensity and spectrum of action), but by its systemic and local tolerance and, last but not least, by its pharmacokinetic properties. A prerequisite for a satisfactory therapeutic success is a high “bioavailability” of the antimycotic drug at the site where the fungus resides. Local concentrations at this site above the minimum inhibitory concentration (MIC) or better minimum biocidal concentration (MBC) values must be achieved and maintained over a sufficiently long period of time. In the case of systemic therapy, high systemic availability is a prerequisite if one is to also obtain high tissue availability at target sites such as the cerebrospinal fluid, brain, lungs, kidney, skin, and vagina. To the contrary, when target sites are accessible to topical treatment, a high local availability and negligible systemic availability are aimed at.

Fluocortolone: Pharmacokinetics and effect on plasma cortisol level

SummaryThe 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.

Pharmacokinetics of Pirazolac - a New Anti-Inflammatory Drug - in Human Volunteers II. Dose Linearity of Plasma Levels and Excretion.

The concentration-time course of pirazolac in plasma and its urinary excretion were investigated in 6 young volunteers (3 males, 3 females) after oral administration of 50, 150, 300, 450, and 600 mg pirazolac as a crystalline suspension at weekly intervals. Only unchanged pirazolac was detected in the plasma. Maximum plasma levels and areas under the plasma level curve increased linearly with the dose. All other pharmacokinetic parameters such as tmax (3 h), oral clearance CL (0.3ml/min/kg) and terminal plasma half life t1/2 (16–18 h) were independent of the dose. A total of 65 % of the dose was renally excreted within 72 hours mainly as pirazolac glucuronide.