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PubMed1980

The interaction of phenobarbital and other anticonvulsants with oral contraceptive steroid therapy.

In a group of 5 women on long-term anticonvulsant and oral contraceptive therapy, the plasma ethynylestradiol (EE) concentration on 50 microgram EE daily was 11.1 +/- 4.5 pg/ml. These values were at the lower end of the range found in normal women in this laboratory taking 30 microgram EE daily (6-190 pg/ml). Four women have been studied prospectively for 3 months, over 1 cycle before and 2 cycles during phenobarbital 30 mg b.i.d. therapy. Significant falls in the plasma EE concentration were seen in two women (from 104.8 +/- 13.4 to 37.7 +/- 2.0 pg/ml and from 125.6 +/- 23.8 to 34.8 +/- 6.7 pg/ml p less than 0.01) and breakthrough bleeding was seen in both women. No changes in plasma concentrations of follicle stimulating hormone, progesterone, norethindrone or norgestrel were seen. There was a significant increase in the sex hormone binding globulin capacity from 100.7 +/- 5.8 to 133.3 +/- 1.2 nmoles/1 (p less than 0.05). These changes are consistent with the known microsomal enzyme inducing effect of phenobarbital.

Adolescent↗
PubMed1981

Pharmacokinetics of norethisterone oenanthate in humans.

The pharmacokinetics of a dose of 200 mg NET-OEN were studied after intramuscular injection into nine subjects. Blood levels of NET and NET-OEN increased rapidly, reaching peaks in most subjects within seven days. At all times after injection, serum levels of NET exceeded those of NET-OEN. The half-life of absorption varied from 5.4 to 22.3 days and the half-life of elimination varied from 7.5 to 22.5 days; there was a significant correlation (R = 0.78) between these two half-lives. There were significant correlations between the absorption half-lives and the peak values of NET and NET-OEN, the time to reach peak values and the time for which NET was detectable in serum. In all subjects NET was detectable in the circulation for a longer time after injection (mean value 74 days) than NET-OEN (mean value 43 days). The time for which the two steroids were detectable in the circulation showed a significant correlation with the elimination half-lives but there was no correlation with the peak values attained, the time taken to reach peak values and bioavailability. There was a two-fold variation between the subjects in the bioavailability of NET, less than 5% of the bioavailable NET was released after day 60.

Absorption↗
PubMed1981

Correlation between the serum norethindrone (NET) levels attained after insertion of a silastic implant releasing norethindrone acetate and the endogenous hormones particularly progesterone.

Six normally menstruating women were inserted each with a single silastic implant-D releasing norethindrone acetate (NETA). The levels of endogenous hormones, FSH, LH, E2 and progesterone, were estimated by radioimmunoassay (RIA) procedures in the control and treatment cycles. In addition, the levels of drug in the serum as norethindrone (NET) which is a major metabolite of NETA were also estimated by RIA procedures in the treatment cycles. In all, 12 treatment cycles were studied. In the initial treatment cycles (1st/2nd or 3rd), the serum NET levels were either 1 ng/ml or above. The LH and FSH showed either normal or suppressed mid-cycle peaks, but the progesterone levels were completely suppressed. In the sixth treatment cycles, the serum NET levels were either 0.5 ng/ml or below. The FSH and LH mid-cycle peaks were lower but distinct while the luteal progesterone levels were of normal ovulatory type. These studies lead us to the conclusion that a serum level of NET of the order of 1 ng/ml is required to bring about suppression of luteal progesterone, either as a result of direct action on the ovary or through suppression of pituitary gonadotropins. When the serum level falls to 0.5 ng/ml or below, the suppressive effect is removed and ovulatory pattern of progesterone returns.

Drug Implants↗
PubMed1982

Plasma protein binding of norethisterone.

Norethisterone (NET) is transported in the blood stream bound to plasma proteins. It is generally believed that only the part of the hormone that is not bound to plasma proteins can exert biological activity. NET binds to albumin and, like other 19-nortestosterone derived progestins, it also binds to sex hormone binding globulin (SHBG). The binding of NET to SHBG was studied in five women during a 21-day treatment cycle with an oral contraceptive containing 3 mg NET-acetate and 50 microgram ethinylestradiol. The total and SHBG-bound concentrations of NET increased in parallel with SHBG during treatment. The fraction not bound to SHBG and the free fraction of NET increased proportionately less, indicating that the total concentrations of NET measured by radioimmunoassay only in part reflect the biologically active fraction of the steroid.

Adult↗
PubMed1982

A simple high-throughput enzymeimmunoassay for norethisterone (norethindrone).

A direct enzymeimmunoassay having the sensitivity required for determining norethisterone concentrations in small aliquots of plasma (10 microliter) has been developed. This assay featured a solid phase antiserum raised against a norethisterone-11 alpha-hemisuccinyl/bovine serum albumin conjugate. The antiserum was coupled to cyanogen bromide-activated magnetisable cellulose, and antibody-bound and free fractions were separated by a simple magnetic device. A norethisterone/horseradish peroxidase conjugate was used as the label; o-phenylenediamine/hydrogen peroxide being the substrate for colour development. The results obtained by this direct EIA, which allowed processing of at least 100 samples per day, were compared with those of a well-validated enzymeimmunoassay featuring solvent extraction and centrifugal separation of antibody-bound and free steroid; the results were in excellent agreement (n = 30; r greater than 0.99) suggesting the usefulness of the simple high-throughput procedure for processing the large sample numbers generated by field investigations and pharmacokinetic studies.

Centrifugation↗
PubMed1982

Serum levels and pharmacokinetics of norethisterone after ingestion of lynestrenol: its relation to dose and stage of the menstrual cycle.

The peak concentration, peak time, the area under the serum concentration time curve (AUC) and half-life of serum norethisterone (NET) after a single application of lynestrenol (LYN) to female volunteers demonstrated that 0.7 mg NET is bioequivalent to 1 mg LYN which is rapidly converted to NET. There was a decrease of the peak values and an increase of half-life of NET during the periovulatory and luteal phase which was, however, not significant due to the great individual differences. The shift of the peak time to longer intervals and the increase of half-life of NET after ingestion of higher LYN doses indicate a certain limitation of the metabolic capacity of the liver. One of the volunteers who complained of nausea and vertigo after the administration of 5 mg LYN, showed the highest serum values of NET. The large interindividual variations of the serum levels of synthetic steroids demonstrate a possible risk of contraceptive safety in women with low steroid levels and possibly a coherence between extremely high serum levels of synthetic steroids and side effects.

Adult↗
PubMed1982

Effect of injectable norethisterone oenanthate (Norigest) on blood lipid levels.

Lipid concentrations were measured in 74 blood samples from 61 women who had been using the injectable contraceptive Norigest (norethisterone oenanthate) for between 2 to 4-1/2 years. There were no significant changes in the concentrations of total cholesterol, total triglycerides and low density and very low density lipoprotein cholesterol but high density lipoprotein cholesterol was significantly reduced. The reduction in serum HDL-C levels was not correlated with either the serum norethisterone concentrations or the length of use of Norigest nor was it affected by obesity or smoking.

Adult↗
PubMed1983

Plasma levels and pharmacokinetics of norethindrone and ethinylestradiol administered in solution and as tablets to women.

Twenty-four normal adult female volunteers were dosed orally with a solution and tablet formulation containing the contraceptive combination of norethindrone (NET, 1.0 mg) and ethinylestradiol (EE2, 0.12 mg) in a crossover bioequivalence study. Blood was sampled sequentially following single oral doses and the plasma separated for analysis of NET and EE2 by specific radioimmunoassays. Comparisons of both drugs following a dose in solution and tablets were made with respect to the following parameters: (a) plasma concentrations at each sample time; (b) maximum plasma concentration (Cpmax); (c) time to maximum plasma concentration (Tmax); (d) total area under the plasma concentration vs. time curve (AUC), and (e) plasma half-life (t1/2). It was found that the tablet and solution doses were bioequivalent with respect to EE2 absorption. However, absorption of NET from solution and tablet doses exhibited significant differences with respect to plasma levels at certain time points as well as AUC (which were higher following the tablet dose), but Cpmax, Tmax and t1/2 were not significantly different. Pharmacokinetic analysis of both drugs following the tablet dose was carried out using a two-compartment open model. The absorption rate constant (ka) and peripheral to central compartment transfer rate constant (k21) were similar for NET and EE2, but statistically significant differences were observed with respect to the distribution rate constant (alpha), the central to peripheral transfer rate constant (k12), the overall elimination rate constant (ke1), and volume of distribution (V1/F). The elimination rate constant (beta) for both drugs showed a difference of borderline statistical significance.

Adolescent↗
PubMed1983

Norethisterone levels in maternal serum and milk after intramuscular injection of norethisterone oenanthate as a contraceptive.

There is concern that the breast-fed infant whose mother is receiving intra-muscular progestogens for contraception will be exposed to significant quantities of the steroid. Norethisterone levels in maternal serum and milk were studied throughout an injection interval after intramuscular administration of 200mg norethisterone oenanthate. Milk samples were taken at the beginning and at the end of the feed. Norethisterone concentrations in milk were very much lower, but declined more slowly, than serum concentrations. Post-suckling concentrations were higher than pre-suckling concentrations. Experiments in adults receiving an oral dose of norethisterone in cow's milk comparable to that ingested by an infant in a day resulted in low serum levels. It is concluded that only very low concentrations of norethisterone would be present in the infant's circulation.

Breast Feeding↗
PubMed1986

Bioequivalence of norethindrone and ethinyl estradiol for two different weight tablets with the same hormonal content.

Two tablets of differing weights, 100 mg (A) and 50 mg (B), of an oral contraceptive drug (OC) were compared with each other and to a solution (C) of the same components. The composition of the OC consisted of 1 mg of norethindrone (NET) and 0.035 mg of ethinyl estradiol (EE2). Both tablets were shown to differ from the solution, which was more rapidly absorbed, but were not significantly different from each other. Formulation means for NET and EE2, for each of the two products, were similar. Application of an interval test for the ratio of computed parameters demonstrated equivalence of the two formulations with respect to 0-24 hr area under the curve (AUC24) and total area under the curve (AUC+o+) for both NET and EE2 and with respect to concentration maximum (Cmax) for EE2. The data support the hypothesis for bioequivalence of the two formulations with respect to total absorption.

Absorption↗
PubMed1986

Pharmacokinetics of oral contraceptive steroids in Egyptian women: studies with Ovral, Nordette and Norminest.

Plasma concentration profiles and pharmacokinetic parameters have been obtained following single dose administration of three commonly used oral contraceptive steroid preparations, Ovral, Nordette and Norminest to Egyptian women. The constituents of the preparations are as follows: Ovral (50 micrograms ethinyloestradiol, EE2 and 500 micrograms levonorgestrel, LNG); Nordette (30 micrograms EE2 and 150 micrograms LNG); and Norminest (35 micrograms EE2 and 500 micrograms norethisterone, NOR). Peak plasma concentrations of EE2 ranged between 116-160 pg ml-1 for Ovral, 55-78 pg ml-1 for Norminest and 30-70 pg ml-1 for Nordette. There was no significant difference in half-life (t1/2), oral clearance (CL) or apparent volume of distribution (Vd). The relative values of the area under the plasma concentration-time curve (AUC) reflected well the different amounts of oestrogen in each preparation. There was no significant difference in t1/2, CL or Vd for LNG in the 2 preparations containing this progestogen. The mean AUC following Nordette (150 micrograms LNG) was 40% of that following Ovral (500 micrograms LNG; p less than 0.001). Comparing pharmacokinetic parameters for the same dose of LNG (Ovral) and NOR (Norminest) showed the AUC to be decreased and CL and Vd increased in the latter group. The study indicates that the kinetic profile of the OCS in healthy Egyptian women are similar to other ethnic populations.

Adult↗
PubMed1988

Assessment of a new low-dose once-a-month injectable contraceptive.

Norethisterone (NET) in combination with mestranol (ME), in a macrocrystalline aqueous suspension that provides sustained release of steroids, was assessed as a once-a-month injectable contraceptive in ten healthy women of reproductive age. The ovarian function was studied before and after the intramuscular administration of 12mg NET plus 1.2mg ME, delivered as crystals of 150 micron average size. Serial blood samples were taken throughout the injection intervals in all women to measure serum progesterone (P), estradiol (E2), and NET. The NET/ME preparation effectively inhibited ovulation in 23 out of the 25 injection intervals studied. The administration of this formulation induced in some women a small degree of follicular maturation not followed by luteal activity. The endometrial bleeding patterns after each injection showed a bleeding-free period of two to three weeks. The overall data demonstrate that the parenteral administration of a macrocrystalline steroid preparation of NET/ME can bring about a sustained release contraceptive system at a substantially lower dose than those currently employed in once-a-month injectable contraception.

Adult↗
PubMed1988

Selectivity in progesterone and androgen receptor binding of progestagens used in oral contraceptives.

The relative binding affinities (RBAs) of four progestational compounds (norethisterone, levonorgestrel, 3-keto-desogestrel and gestodene) for the human progesterone and androgen receptors were measured in MCF-7 cytosol and intact MCF-7 cells. For the binding to the progesterone receptor, both Org 2058 and Org 3236 (or 3-keto-desogestrel) were used as labelled ligands. The following ranking (low to high) for the RBA of the nuclear (intact cells) progesterone receptor irrespective of the ligand used is found: norethisterone much less than levonorgestrel less than 3-keto-destogestrel less than gestodene. The difference between the various progestagens is significant with the exception of that between 3-keto-desogestrel and gestodene, when Org 2058 is used as ligand. For the cytosolic progesterone receptor, the same order is found with the exception that similar RBAs are found for gestodene and 3-keto-desogestrel. The four progestagens clearly differ with respect to binding to the androgen receptor using dihydrotestosterone as labelled ligand in intact cells; the ranking (low to high) is: norethisterone less than 3 keto-desogestrel less than levonorgestrel and gestodene. The difference between 3-keto-desogestrel and levonorgestrel or gestodene is significant. The selectivity indices (ratio of the mean RBA for the progesterone receptor to that of androgen receptor) in intact cells are significantly higher for 3-keto-desogestrel and gestodene than for levonorgestrel and norethisterone. From these results we conclude that the introduction of the 18-methyl in norethisterone (levonorgestel) increases both the binding to the progesterone and androgen receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Line↗
PubMed1989

Bioequivalence of two oral contraceptive drugs containing norethindrone and ethinyl estradiol.

Two oral contraceptive drugs, Formulation A and Formulation B, both of similar hormonal content, were compared with each other to determine if they were bioequivalent. Both drugs contain 1 mg of norethindrone (NET) and 0.035 mg of ethinyl estradiol (EE). Application of an interval test for the ratio of the computed parameter means demonstrated equivalence for the two formulations with respect to the 0-24 hour area under the plasma level versus time curve (AUC24), the total area under the curve (AUCtot) and for the maximum plasma concentration (Cmax) for both ethinyl estradiol and norethindrone. The data support the hypothesis for bioequivalence of the two formulations with respect to total absorption.

Adult↗
PubMed1991

Interchangeability of low-dose oral contraceptives. Are current bioequivalent testing measures adequate to ensure therapeutic equivalency?

Current Food and Drug Administration guidelines for assessing the differences in bioavailability between generic oral contraceptives and brand-name products are inadequate to ensure therapeutic equivalence. The guidelines do not take into account those women who may have blood levels of active ingredients well outside the range of acceptability. Due to the narrow therapeutic range of steroids, these women may become pregnant or experience an increased incidence of breakthrough bleeding. Furthermore, oral contraceptive packaging is unique to each manufacturer, and any change in brands (and therefore packaging) can easily negate the sequential administration of the appropriate tablet. These are among the reasons proposed for placing oral contraceptives in the critical drug category, in which generic substitution and interchangeability of products should not be allowed.

Biological Availability↗