Bioavailability of norethisterone acetate alone and in combination with estradiol administered in single or multiple oral doses to postmenopausal women.

OBJECTIVES: Twenty-four postmenopausal women were randomly allocated to a cross-over trial for an investigation of the pharmacokinetics of norethisterone acetate (NETA; 0.5 mg), administered alone or in combination with estradiol (E2; 1 mg), both after a single oral dose. In a second trial, the above combination of 0.5 mg NETA with 1 mg E2 was administered daily for 28 days. METHODS: Plasma levels of NET, E2, estrone (E1) and estrone sulphate fraction containing an admixture of estrone glucuronide (E1S/E1G) were measured by radioimmunoassay at various intervals up to 72 h in the first trial and at the same intervals after the 28th day in the second trial. RESULTS: In the first, single-dose trial, pharmacokinetic parameters of NET were similar for NETA administered alone and its combination with E2. There was no statistically significant difference in the area under curve values AUC0-24 and AUC0-infinity and no apparent major differences were observed for other pharmacokinetic parameters. No carry-over effects due to the cross-over design were seen. The multiple dosage in the second trial did not cause any major changes in the pharmacokinetic parameters of NET, except for the AUC0-24 and AUC0-infinity values which were significantly higher than those seen in the first trial. The levels of E2 exhibited, shortly after the intake of E2, a rapid burst. The levels gradually decreased to a nadir followed by an increase to the main peak and by the subsequent elimination phase. The difference between the peak and nadir levels was significant (P < 0.05) in the second, multiple-dose trial. This bimodal pattern was not observed in earlier studies. The main metabolite of E2 was E1S/E1G, followed by E1, as could be seen from the AUC0-infinity values. These were, in both trials, approximately 300 and 7-times higher for the E1S/E1G and E1, respectively, than those for E2. For all analytes, the AUC0-24 values were significantly higher in the second trial than those found in the first trial, indicating accumulation upon repeated administration. Pharmacokinetics of all analytes remained linear in the second trial, as follows from the statistically established equality of AUC0-24 found in the second, multiple-dose trial with AUC0-infinity in the first, single-dose trial. The absorption half-life and t-max values of E1S/E1G appeared to be considerably shorter than those of E1 in both trials. CONCLUSIONS: The bioavailability of NET was not influenced by its combination with 1 mg E2. The most abundant metabolite of E2 was the E1S/E1G fraction, which may have served as the main source of E2 and other estrogens due to metabolic interconversions during the absorption and elimination phases.

Assays of antibodies to a C-terminal peptide or the entire beta-subunit of human chorionic gonadotropin.

Antibodies were assayed in serum samples obtained from rabbits or women immunized with a vaccine based on a C-terminal peptide (109-145; CTP) of the beta-subunit of human chorionic gonadotrophin (hCG) with use of a ligand-binding assay. In rabbit samples, two types of assay were used. The first "homologous" type was based on CTP as tracer and standard. In the second "heterologous" type, directly reflecting the hCG-neutralizing potency, hCG was used as tracer and standard. The equilibrium constants of antibodies were substantially higher in the homologous than in the heterologous assay, indicating that the fit of hCG to the antibodies was worse than that of CTP. This was further confirmed by very low cross-reaction values of hCG. In addition, hooks occurred in Scatchard plots when the heterologous assay type was used, both with rabbit and human samples. However, a high correlation between the results of the homologous and heterologous assay was observed (r = 0.97; P < 0.05). Therefore, it is envisaged that the possibility of using the homologous, analytically less complex assay will be further investigated in future clinical studies. Antibodies raised in women to the beta-subunit of hCG had equilibrium constants higher by one to two orders of magnitude than those of the anti-CTP antibodies. The present definition of a threshold pregnancy-preventing level of antibodies disregards their avidity. It is suggested that in future studies, the problem of varying avidity could be solved by individually adjusting the threshold levels with respect to antibody avidity.

The effect of small doses of progesterone released from two types of vaginal rings on ovarian activity and bleeding patterns during the first postpartum year.

A total of 20 breastfeeding women used progesterone-releasing vaginal rings for up to 12 months. The women were divided into two groups, one (n = 9) using rings with an initial release rate of 5 mg/24 h, the other (n = 11) with a release rate of 20 mg/24 h. Individual women started to give breast milk supplements and ceased to breastfeed after various periods of time. Urinary estrone and pregnanediol glucuronide levels were measured by radioimmunoassay three times weekly during the entire trial. Individual diary cards were used to register bleeding and spotting. A significantly higher concentration of pregnanediol glucuronide was seen when the 20 mg/24 h ring was used in the lactation period, in comparison with the 5 mg/24 h ring. In the post-lactation period, pregnanediol glucuronide levels dropped when the 20 mg/24 h ring was used. Estrone glucuronide levels increased after the termination of breastfeeding, indicating an enhanced suppression of ovarian activity in the lactation period with both rings. Although the degree of suppression was dose-related, both rings were likely to offer a sufficient contraceptive effect in the lactation period. No significant changes were observed when milk supplements were added to breastfeeding. The use of the 20 mg/24 h ring resulted in a much better bleeding pattern (significantly less bleeding days) than the 5 mg/24 h ring during the lactation period. In the post-lactation period, the 20 mg/24 h ring the bleeding because much worse than in the lactation period.(ABSTRACT TRUNCATED AT 250 WORDS)

PIP: In Sweden, 23 lactating women 6-8 weeks postpartum accepted a vaginal ring that initially releases either 5 mg or 20 mg progesterone/day. Researchers followed 20 women for 1 year and examined the urinary glucuronides and the metabolites of estradiol and progesterone, estrone and pregnanediol, to observe changes in ovarian activity. They also documented bleeding patterns. Women using the 20 mg/24 hour ring had a lower bleeding rate during the lactation period than the postlactation period (6.1 vs. 23.6 days; p 0.01). Bleeding rates dropped somewhat among women using the 5 mg/24 hour ring, but did not differ significantly between these two periods (22.7 vs. 20.2 days). Estrone glucuronide levels rose significantly in both groups after lactation ceased (5 mg/24 hour ring: 44.8 vs. 101.8 nmol/l, p 0.05; 20 mg/24 hour ring: 22.5 vs. 42.4 nmol/l, p 0.01), suggesting increased suppression of ovarian activity during lactation. The 5 mg/24 hour ring induced higher estrone glucuronide levels both during and after lactation than the 20 mg/24 hour ring (44.8 vs. 22.5 nmol/l and 101.8 vs. 42.4 nmol/l, respectively; p 0.01), indicating a dose-related degree of ovarian activity suppression. For both vaginal rings there were no differences in the degree of ovarian suppression between the full breast feeding period and the breast feeding with supplementation period. Pregnanediol glucuronide levels were much higher in users of the 20 mg/24 hour ring during lactation than after lactation (9.2 vs. 6.1; p 0.01). The increase in pregnanediol glucuronide levels in users of the 5 mg/24 hour ring after lactation had ceased was not significant (4.6 vs. 6.6 nmol/l). During lactation, users of the 20 mg/24 hour ring had higher levels than users of the 5 mg/24 hour ring (4.6 vs. 9.2 nmol/l; p 0.05), while, during the postlactation period, the levels were similar (6.6 vs. 6.1 nmol/l). In conclusion, the 20 mg/24 hour ring is preferable during lactation, and if users are concerned about bleeding after lactation ends, they can switch to another contraceptive.

Quantitative analysis of steroid hormone receptors and their messenger ribonucleic acids.

Ligand binding will remain the basic technique for receptor determinations in many laboratories. It can easily be set up and it is inexpensive. It has, however, the disadvantage of requiring relatively large amounts of tissue or cultured cells, if the proper multipoint measurements for Scatchard plots are to be done. Furthermore, each of the bound/free separation techniques mentioned above has its own caveat that has to be respected if analytically correct results are to be obtained. The great advantage of receptor immunoassays is their technical simplicity and the possibility of measuring a single dose of a receptor sample (in contrast to the Scatchard plot approach in ligand-binding assays). The possibility of using a single dose (even if assayed in duplicate) is a very valuable feature in all instances when only small tissue samples are available for assay. It would be very attractive for many laboratories to set up their own receptor immunoassays. The availability of suitable antibodies may not be a major obstacle. However, the necessity of possessing a supply of a highly purified receptor standard preparation may pose a problem. This is why commercial kits seem to be used so frequently. The analysis of receptor mRNA is a complement of or alternative to receptor quantitation. It must be realized, however, that special skills, as well as a molecular biology laboratory environment and equipment, are required for successful analytic work in this area. Solution hybridization is to be preferred as an approach to obtain results of a quantitative character. However, the specificity of hybridization should be checked by Northern blots. The same is true for dot/slot hybridization, which is a suitable method for semiquantitative assessments of a series of samples. Last but not least, the in situ hybridization provides invaluable information on the tissue and cell distribution of the mRNA analyzed.

Studies on a vaginal ring releasing levonorgestrel at an initial rate of 27 micrograms/24 h when used alone or in combination with transdermal systems releasing estradiol.

Vaginal rings releasing levonorgestrel (L-NOG) at an initial rate of 27 micrograms/24h were studied in a group of 24 normally menstruating women during three months (i.e., during three four-week segments). Each segment consisted of three weeks with the vaginal rings in situ followed by a treatment-free period of one week. The women were divided into three groups (8 subjects each). The first group received vaginal rings only, the second and third groups were treated, in addition, with transdermal systems (patches) releasing estradiol at a rate of 50 and 100 micrograms/24h, respectively. Peripheral blood samples were withdrawn three times weekly (Monday, Wednesday and Friday) during a pretreatment cycle and during the following three months of treatment. The levels of L-NOG, estradiol and progesterone were analyzed by radioimmunoassay techniques. In all subjects, endometrial biopsies were taken in a control cycle and during the last days with vaginal rings in situ in segments II and III. The treatment with estradiol did not significantly influence L-NOG levels. Considerable differences in the L-NOG levels between the subjects of the same group were observed. Fluctuation in ovarian reaction within groups was also large. Nevertheless, estradiol noticeably increased the proportion of anovulatory cycles; the total number of anovulatory segments was 5, 9 and 19 (out of 24) in the groups "No estradiol", "50 micrograms/24h estradiol" and "100 micrograms/24h estradiol", respectively. A morphometric study of the endometrium indicated a significant decrease in the diameter of glands. This change was due to L-NOG alone, but it seemed to be accentuated by the exogenous estradiol. The occurrence of glandular mitoses increased in both groups receiving estradiol in a dose-dependent manner, indicating an increased endometrial proliferation. The treatment with estradiol did not significantly alter the bleeding pattern.

Pharmacokinetic and pharmacodynamic effects of vaginal rings releasing levonorgestrel at a rate of 27 micrograms/24 hours: a pilot study.

The pharmacokinetic and pharmacodynamic effects of vaginal rings releasing levonorgestrel (L-NOG) at an initial rate of 27 micrograms/24 h were studied in a group of 12 normally menstruating women during 90 days of continuous use (i.e., during three 30-day treatment segments). Blood samples were drawn immediately before insertion, 15 and 30 min, as well as 1, 2, 4, 8, 12 and 24 h after insertion of the rings, and thereafter three times weekly throughout the study for the analysis of L-NOG, estradiol, progesterone and sex hormone-binding globulin (SHBG). Endometrial biopsies were obtained for a morphometric analysis in a pre-treatment (control) cycle and in the 6th and 10th weeks of treatment. The peak of average L-NOG levels was reached within two hours after the insertion of rings. Until 24 h after insertion, the levels did not change significantly. Thereafter, a decrease at a rate of 0.2% per day was initiated. The L-NOG and SHBG levels were highly correlated. This was seen for both the pre-treatment SHBG vs L-NOG (r = 0.96) and the treatment SHBG vs L-NOG levels (r = 0.92). There was a significant (p < 0.001) decrease of SHBG levels due to treatment. During the total of 36 treatment segments, a normal ovarian function was seen in 47% of the segments. The women were anovulatory and had an inadequate lutal function in 28% and 25% of segments, respectively. No correlation between the L-NOG levels and ovarian reaction to treatment was found. The use of L-NOG induced significant changes in the endometrium; the number of glands/mm2 decreased after 6 (p < 0.02) and 10 weeks of use (p < 0.01). Also, the diameter of glands and the occurrence of vacuolated cells decreased significantly (p < 0.02 and p < 0.005, respectively). None of the endometrial parameters or dating was correlated with the ovarian reaction to treatment, indicating independent endometrial effects of L-NOG.

Termination of early pregnancy with ZK 98,734: pharmacokinetic behaviour and clinical effect.

The antiprogestin RU 486 (mifepristone) is highly effective in inducing early abortion in women only if the compound is combined with a prostaglandin analogue. A new related antiprogestin, ZK 98,734, has been reported in animal studies to be much more potent as an abortifacient than mifepristone, concomitant with less antiglucocorticoid activity. The aim of the present two-centre study was to explore the abortifacient efficacy and plasma concentrations of ZK 98,734 in women seeking abortion. A total of 96 pregnant women with amenorrhoea of < 49 days were treated with oral doses of 12.5, 25, 50 or 100 mg ZK 98,734 twice daily for 4 days. The overall rate of complete abortion and continuing live pregnancies was 68 and 20% respectively, i.e. results comparable with treatment with mifepristone alone. No dose-response relationship was noted. In patients with complete abortion, signs of luteal dysfunction in terms of oestradiol and progesterone production were evident on the fourth treatment day, in contrast to patients with failures. Increased amounts of cortisol and prolactin were found during treatment both in successfully treated patients and failures, whereas aldosterone values remained unaffected. The effect on cortisol may indicate some antiglucocorticoid activity in the human. The concentrations of ZK 98,734 in peripheral blood after 25, 50 and 100 mg twice daily for 4 days were similar. The values were slightly above 0.5 mumol/l on the second day of treatment. Maximal concentrations of 0.7 mumol/l were seen on treatment day 4. Plasma concentrations of ZK 98,734 did not differ in cases of complete abortion and failures.(ABSTRACT TRUNCATED AT 250 WORDS)

Progesterone-releasing vaginal rings for use in postpartum contraception. II. Pharmacokinetic profiles in women.

Vaginal rings releasing progesterone with 3 different initial release rates (5, 8 and 20 mg/day) were used by 11, 10 and 10 women, respectively. The period of insertion was 90 days. The 5 and 8 mg/day rings consisted of a core loaded with progesterone, the 20 mg/day ring contained progesterone homogeneously distributed throughout the mass of the ring. Notwithstanding these differences, the total progesterone levels (areas under curve) were directly related to the release rates. So were the rates of decrease of progesterone levels during the 90 days of insertion of the ring. They were 25, 31 and 47% for the rings releasing 5, 8 and 20 mg/day, respectively.

PIP: Physicians from Karolinska Hospital in Stockholm, Sweden and a scientist form WHO in Geneva, Switzerland examined the pharmacokinetic behavior of progesterone released from vaginal rings over 90 days in 31 women who took a combined oral contraceptive (OC) each day. The OC suppressed ovarian function. The physicians inserted a vaginal ring with a core which released 5 mg progesterone/day in 11 women and a 8 mg/day ring in 10 women. The inserted a 20 mg/day vaginal ring with progesterone homogeneously distributed throughout the mass of the ring in 10 women. Total circulating progesterone levels were significantly correlated with initial release rates of the 3 vaginal rings (p.001). Further, at the end of 90 days, progesterone levels decreased significant from initial levels in all women (25% for the 5 mg/day vaginal ring, 31% for the 8 mg/day ring, and 47% for the 20 mg/day ring). These results matched those of earlier in vitro studies with the same vaginal rings. Researchers next need to determine which type of vaginal ring and release rate optimally protects against pregnancy and induces an acceptable bleeding pattern. WHO promotes research in vaginal rings saturated with progesterone as a possible contraception for postpartum mother since progesterone does not adversely affect breast fed infants. Furthermore progesterone suppresses ovulation.

Plasma estriol levels after intramuscular injection of estriol and two of its esters.

Twelve female volunteers from Berlin and 9 from Stockholm, all using a contraceptive pill (30 micrograms ethinyl estradiol and 150 micrograms levonorgestrel), received an intramuscular injection of estriol (E3; 1 mg in oil) on day 5 of withdrawal bleeding. Blood samples were collected at increasing time intervals during 4 weeks. Three months later, on day 5 of their withdrawal bleeding, 6 women were given intramuscularly (in oil) estriol 3,17-dipropionate (E3-prop) and 15 women estriol 3,17-dihexanoate (E3-hex). The doses were equivalent to 5 mg of estriol, i.e. 6.94 and 8.90 mg, respectively. Blood samples were collected during a period of 9 weeks. Estriol was analyzed by radioimmunoassay in all plasma samples. The average half-life of E3 ranged from 1.5 to 5.3 h after the administration of E3. It was 12.7 h and between 187 and 221 h after the administration of E3-prop and E3-hex, respectively. The average areas under the curve (in nmol.l-1.h) of E3 were between 82.5 and 161 after the administration of E3-prop or E3-hex, and between 27.1 and 37.9 when E3 had been given. As E3 was administered in a 5-fold lower dose than the esters, the areas under curve appeared to be comparable. Thus, the total exposure to E3 seemed to be almost independent of the type of E3 derivatization, while the time and intensity of exposure were very different.

Estimation of true values in radioimmunoassays.

We tested the accuracy of radioimmunoassays for two hormones, progesterone and estradiol, in relation to the use of two different antisera in each assay and to the degree of purification from plasma before the assay was done. Each analyte was assayed either in a diethyl ether extract, in a zone eluted from a Sephadex LH-20 chromatographic column, or in fractions of a chromatographic zone (from Sephadex LH-20 or Celite) that passed a test of "radiochemical purity." Statistically indistinguishable results were obtained in the assay of radiochemically pure fractions of both analytes, irrespective of the antiserum used. In addition, one of the antisera from each hormone gave equivalent results in the radioimmunoassay of ether extracts, even with no preceding chromatography. We demonstrated in this way that results obtained with use of highly specific antisera may, after a single chromatography, but even without any chromatographic purification, be as nearly accurate and as closely reflect the true value as those obtained in the assay of radiochemically pure hormones, an assay that has a character of a reference method (as defined by the IFCC).

Relative binding affinity of various progestins and antiprogestins to a rabbit myometrium receptor.

Relative binding affinity (RBA) of various progestins and antiprogestins to a cytoplasmic receptor prepared from the myometrium of estrogenized immature female rabbits was investigated. The cytosol was incubated with tritiated promegestone (3H-R5020) in the presence of various concentrations of non-radioactive promegestone (R5020) as standard on the one hand, and several progestins and antiprogestins on the other hand. The incubate was subjected to isoelectric focusing in slabs of polyacrylamide gel and the bound radioactivity in the peak of the receptor was measured, RBA was expressed as a percentage given by the ratio of those concentrations of R5020 and the compound tested which were required for a 50% displacement of 3H-R5020. The RBA's of the progestins tested were in the following order: R5020 greater than norethisterone greater than levonorgestrel greater than progesterone greater than medroxyprogesterone acetate. There was practically no binding to dextronorgestrel, cortisol, testosterone, and estradiol. In the group of antiprogestins, there were no significant differences in the RBA of the compounds RU 486, RU 42633 (monodemethyl derivative of RU 486) and ZK 98.734. Another two derivatives of RU 486, RU 42848 (didemethyl) and RU 42698 (propargyl), had lower RBA's than RU 486. Two 13,17-stereoisomers related to the above antiprogestins (i.e. compounds ZK 98.299 and ZK 115.716) exhibited a decreased RBA in comparison with the compound ZK 98.734.

Immunometric assay for lutropin (hLH) based on the use of universal reagents for enzymatic labelling and magnetic separation and monitored by enhanced chemiluminescence.

A solid-phase immunometric assay of human lutropin (hLH) is described. Two different anti-hLH antibodies were utilized as capture antibodies, and anti-IgG antibodies covalently coupled to magnetic particles and horseradish peroxidase, respectively, served as 'universal' detection reagents. An anti-hLH antibody raised in rabbits was incubated with a goat anti-rabbit IgG covalently bound to magnetic particles. The resulting complex was added to a separately incubated mixture of hLH and monoclonal anti-hLH antibody. Following incubation, the immunocomplex was sedimented in a magnetic field and the supernatant discarded. Finally a sheep anti-mouse antibody (F(ab')2 fragment) conjugated to horseradish peroxidase as label was added. Following a further incubation, the particles were sedimented in the magnetic field and washed. The hLH content of the sample was quantitated by measuring 'enhanced chemiluminescence'. The sensitivity of the assay was 2.5 +/- 0.9 IU/l (mean +/- SD), the within-run variation ranged from 7.9 to 11%, the between-run variation from 12.9 to 19.8%. Cross-reaction with hFSH or hTSH could not be detected, but was approximately 0.1% with hCG. The results correlated well with those obtained by radioimmunoassay (r = 0.84).

Does endogenous sex hormone binding globulin influence the contraceptive effect of levonorgestrel?

On the basis of four previous clinical studies a direct relationship of the contraceptive effect of levonorgestrel expressed as a suppression of ovarian function) to individual levels of sex hormone binding globulin may be assumed. The rationale of this dependence seems to be the protection against metabolic degradation which is provided by sex hormone globulin to levonorgestrel.

The interaction between sex hormone binding globulin and levonorgestrel released from Norplant, an implantable contraceptive.

Two-hundred-and-eighty Indonesian women were provided with Norplant, a levonorgestrel-releasing implant. At various time intervals, up to 5 years after Norplant insertion, levonorgestrel and sex hormone binding globulin (SHBG) were assayed in blood plasma. After an initial burst of approximately 7 nmol/l, the levels of levonorgestrel rapidly decreased during the first month. The decrease continued to a nadir (1.1 nmol/l) which was reached 10 months later. The decrease was followed by an increase to a broad peak of 1.5 nmol/l which was reached 2 years after insertion. Thereafter, a slow-decrease at a rate of approximately 18 pmol/month was seen. SHBG levels decreased significantly already 1 week after insertion. A nadir of levels (25 nmol/l) was reached 3 months later. The levels increased slowly again and remained constant (32 nmol/l) from about 15 months to 5 years. During the entire period of study highly significant correlations of levonorgestrel with SHBG were seen. In another group of 25 women the levels of levonorgestrel and SHBG were studied before and one week after insertion of Norplant. A significant correlation (r = 0.77) was found between the preinsertion levels of SHBG and postinsertion levels of levonorgestrel.

PIP: 288 Indonesian women were provided with Norplant a levonorgestrel-releasing implant. At various time intervals, up to 5 years after Norplant (R) insertion, levonorgestrel and sex hormone binding globulin (SHBG) were assayed in blood plasma. After an initial burst of approximately 7 nmol/1, the levels of levonorgestrel rapidly decreased during the 1st month. The decrease continued to a nadir (1.1 nmol/1) which was reached 10 months later. The decrease was followed by an increase to a broad peak of 1.5 nmol/1 which was reached 2 years after insertion. Thereafter, a slow decrease at a rate of approximately 18 pmol/month was seen. SHBG levels decreased significantly already 1 week after insertion. A nadir of levels (25 nmol/1) was reached 3 months later. The levels increased slowly again and remained constant (32 nmol/1) from about 15 months to 5 years. During the entire peiod of study highly significant correlations of levonorgestrel with SHBG were seen. In another group of 25 women the levels of levonorgestrel and SHBG were studied before and 1 week after insertion of Norplant. A significant correlation (r=0.77) was found between the preinsertion levels of SHBG and postinsertion levels of levonorgestrel.

Biases in the assays of steroids and their binding proteins.

Many immunoassays exhibit a bias. In such assays, the results are inaccurate, i.e. they deviate from the true value. The biases are mostly due to interfering compounds originating from the biological material assayed and/or from reagents. Sometimes systematic errors in calculation are also involved. The magnitude of the bias should be determined for every assay method, in order to make possible an assessment of reliability of the method. Biases frequently occur also in the measurements of steroid binding proteins, such as receptors, sex hormone binding globulin, corticosteroid binding globulin, etc. These biases are mostly due to the assumption that the measurements are performed under saturation conditions. These biases can be avoided by conducting the measurements at several concentrations of the ligand and by an appropriate correction for non-specific (low affinity) binding. In the assays of "free" steroids, biases are frequently encountered because of the disturbance of equilibrium in the course of the measurement proper. These biases can be minimized by a careful choice of experimental conditions.

Plasma levels of antiprogestin RU 486 following oral administration to non-pregnant and early pregnant women.

RU 486 is a synthetic steroid which acts as an antiprogestin at the receptor level. The clinical usefulness of the compound for menstrual regulation and termination of early pregnancy is currently being evaluated. The aim of the present study was to determine the plasma levels of RU 486 following the oral administration of the compound to 42 pregnant and 10 non-pregnant women. The levels of RU 486 were measured by a radioimmunoassay method which uses chromatography on Sephadex LH 20 columns. The identity of the compound assayed as RU 486 was confirmed, but the presence of small amounts of two highly cross-reacting metabolites (monodemethyl and didemethyl RU 486) in the analyzed fractions could not be excluded. Following the ingestion of a single tablet containing 25 and 50 mg of the compound, a peak plasma value of approximately 3.5 to 4.0 mumol/l in both the pregnant and non-pregnant subjects was reached one to two hours later. The half-lives of elimination were about 20 hours in both the pregnant and the non-pregnant women. Following the repeated oral administration of 50, 100 or 200 mg of RU 486 daily for four days, maximum plasma levels of 2.9, 4.5 and 5.4 mumol/l, respectively, were found. Thus, the increase in plasma levels was not directly proportional to the increase in the dose. No accumulation of RU 486 in the plasma was found, even when the duration of treatment was prolonged to six days. The data partly explain the reported lack of relation between ingested dose and frequency of induced abortion and they may be useful for designing future studies on the use of compound to prevent implantation, induce menstruation or terminate an early pregnancy.

Pharmacokinetics of the progesterone antagonist 17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)-17 alpha-(1-propynyl) estra-4,9-dien-3-one in the rabbit.

Pharmacokinetic characteristics of compound RU 486 (17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)-17 alpha-(1-propynyl)estra-4,9-dien-3-one) were investigated in 6 immature estrogenized female rabbits. A dose of 3.4 mg/kg was administered either intravenously or orally, in both cases together with 3H-RU 486 (13.4 muCi/kg). The concentration of RU 486 was measured in blood plasma following isolation by thin-layer chromatography. The concentration of ether-extractable metabolites was obtained from the difference between the total ether-extractable radioactivity and the radioactivity of the isolated RU 486. Following the i.v. administration it was found that the disposition of RU 486 could be described by a biexponential curve. The half-life of the slow disposition phase of RU 486 was significantly lower (t1/2 = 52 min: P greater than 0.05) than those of RU 486 metabolites (t1/2 = 99 min). High apparent volumes of distribution of RU 486 and RU 486 metabolites (5.8 and 6.0 l/kg, respectively) indicated a high extravascular binding. Following the oral administration in oil solution, RU 486 could not be found in plasma in reliably detectable amounts due to a poor absorption and a probable first-pass effect. In the measurements of the "total RU 486" (sum of RU 486 and ether-extractable metabolites), a similar rate of terminal disposition was found for both routes of administration.

Pharmacokinetic studies with a vaginal delivery system releasing levonorgestrel at a near zero order rate for one year.

Vaginal rings releasing approximately 20 micrograms levonorgestrel per 24 hours were used continuously by ten women for a period of one year. Circulating plasma levels of levonorgestrel (L-NOG) were measured every second week. Steroid hormone binding globulin (SHBG) levels were measured in the first and last four blood samples drawn. A linear relationship between the logarithms of L-NOG concentrations and duration of use was found, indicating an exponential character of decrease in L-NOG levels during the study year. An average of 72% of the mean initial levels of L-NOG was found in the circulation after 6 months' and 52% after one year's use. The L-NOG levels decreased daily by 1.1 pmol/l (0.13%) on the average. The SHBG levels were not influenced by the long-term exposure to L-NOG. The initial SHBG levels were significantly correlated (r = 0.88; P less than 0.001) to the initial L-NOG levels. The rings were well tolerated. Only in two of the ten subjects did the average number of bleeding days per month increase from a pretreatment value of 4.5 days per month to 8.3 and 9.5 days per month, respectively.