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At least 19 recordsLinked to original sources
PubMed1978

Radioimmunoassay of norethindrone : serum levels of norethindrone in lactating women after insertion of a single Silastic implant releasing norethindrone acetate.

A specific radioimmunoassay was developed for the estimation of norethindrone levels in the serum of lactating women. A conjugate of norethindrone-3-BSA was synthesized and antiserum raised against it in rabbits. The antiserum showed high affinity (1.5 x 10(9)M/L) and titer and was specific. The sensitivity of the assay was 125 pg/ml serum. Serum levels of norethindrone were estimated in 25 lactating women, inserted with subdermal implant releasing about 150 ug of norethindrone acetate daily. The norethindrone levels were initially high in the first two months. From there onwards the levels of norethindrone remained constant with an average value of 1.0 ng/ml up to six months. These values were comparable to those obtained in non-lactating women. Thus, lactation does not seem to alter or affect the release of norethindrone acetate from the subdermal implant or its metabolism.

Animals↗
PubMed1990

Dissolution testing of norethindrone:ethinyl estradiol, norethindrone:mestranol, and norethindrone acetate:ethinyl estradiol combination tablets.

Dissolution of oral contraceptive combination products from six manufacturing firms was studied utilizing the rotating basket method at 100 rpm in 600 mL of 0.1 M HCl and 0.02% sodium lauryl sulfate (SLS). Most of the combination products of norethindrone (NE):ethinyl estradiol (EE) dissolved satisfactorily in water using the paddle method which was first proposed by U.S.P., whereas three of 18 tested products showed better dissolution in acidic aqueous medium containing SLS. Acidic medium with surfactant was also found to be suitable for combination products of norethindrone (NE):mestranol (ME) and norethindrone acetate (NEAc):ethinyl estradiol (EE). A modified U.S.P. assay procedure, a reversed-phase high-performance liquid chromatographic (HPLC) method with a mobile phase of acetonitrile and phosphate buffer, was used to analyze NE and EE concurrently. The NEAc and ME were analyzed separately in these combination products. The NEAc was found to hydrolyze to some extent (approximately 20% in 8 h) in acidic dissolution medium at room temperature, but less so at 4 degrees C. The NE was identified as the sole degradation product of NEAc hydrolysis and was also measured to account for the total amount of NEAc dissolved. A simple dissoluting testing method which utilizes a single dissolution medium was applicable for all oral contraceptive combination tablets surveyed.

1-Propanol↗
PubMed2003

The effect of food on the bioavailability of norethindrone and ethinyl estradiol from norethindrone acetate/ethinyl estradiol tablets intended for continuous hormone replacement therapy.

As part of the development of a combination product containing norethindrone acetate and low-dose ethinyl estradiol for continuous hormone replacement therapy in postmenopausal women, a study was conducted to determine the effect of a high-fat meal on the bioavailability of norethindrone and ethinyl estradiol from tablets containing 1 mg norethindrone acetate/10 micrograms ethinyl estradiol. Eighteen healthy postmenopausal women participated in an open-label, single-dose, randomized, three-way crossover study in which 2 x 1/10 norethindrone acetate/ethinyl estradiol tablets were administered fasting and with a high-fat breakfast, and the same dose was administered in solution. Following each treatment, serial blood samples were collected for 48 hours, and plasma ethinyl estradiol and norethindrone concentrations were determined by a validated gas chromatography/mass spectrometry (GC/MS) method. Individual plasma ethinyl estradiol and norethindrone pharmacokinetic parameters were calculated by noncompartmental methods for each treatment and analyzed by ANOVA to obtain differences between least squares treatment mean values and associated 90% confidence intervals. Rates of ethinyl estradiol and norethindrone availability from tablets administered with food were slower than availability rates from tablets administered while fasting. Systemic exposure to ethinyl estradiol was unaffected by administration of tablets with food, whereas exposure to norethindrone increased by 27%. Because administration of norethindrone acetate/ethinyl estradiol 1/10 tablets with a high-fat meal did not decrease systemic exposure to norethindrone and ethinyl estradiol, this formulation can be taken without regard to meals.

Aged↗
PubMed1983

Norethindrone antisera: anomalous cross-reactivities with use of 3H-tetrahydro-reduced norethindrone as radioligand.

Anomalous cross-reactions with the dihydro- and tetrahydro-reduced metabolites of norethindrone were observed utilizing antisera raised against norethindrone-3-bovine serum albumin. Whereas displacement of 3H-norethindrone from the antiserum by the metabolites was generally minimal, where one of the metabolites was used as radiotracer, displacement by the metabolites was equal to or greater than that achieved by norethindrone. This unexpected finding was examined for its usefulness in developing a radioimmunoassay system for norethindrone metabolites in plasma. The sensitivity of the resulting standard curve was such as to permit quantitation of pg amounts of the reduced metabolites.

Animals↗
PubMed1983

Norethindrone in serum after use of an oral contraceptive containing norethindrone acetate.

The availability of norethindrone (NET) in serum was studied in 8 women after daily administration of a combination oral contraceptive pill (MinovlarR) containing 1 mg norethindrone acetate (NETA) and 50 micrograms ethinyl estradiol (EE2) from day 5 to day 25 of the menstrual cycle. The pill was taken daily at 9:30 a.m. after a light breakfast and blood samples were collected at 3 hr on alternate days and at 24 hr on other days after ingestion of the pill. On day 12 or day 15 of the first treatment cycle, serial blood samples were also collected at 1/2, 1, 2, 4, 6, 8 and 24 hr after taking the pill. Serum NET levels were estimated by the radioimmunoassay (RIA) technique. The plot of serum NET concentration versus time (0-24 hr) profile showed a rapid absorption of steroid and a peak NET concentration (18.3 +/- 4.8 ng/ml) reached at 2 hr after ingestion of the pill. By linear regression analysis of data (y = 0.27 + 0.12x; r = 0.95), it was observed that the serum NET level was initially about 1 ng/ml. Thereafter, it increased by 0.12 ng/ml per day up to 3.5 ng/ml by the end of 21 days' treatment with oral pills. The serum NET concentration decay slope fitted a two-compartment open model with an initial rapid decay (half-life of 1.2 +/- 0.1 hr) followed by a slower beta-phase with a half-life of 8.5 +/- 1.5 hr. The study revealed that there was an accumulation of norethindrone in plasma during the treatment period and this suggests the possibility of exploring a reduction in the dose of this preparation so as to achieve the optimum NET concentration for contraception, and thereby avoiding unwanted steroid accumulation in the plasma of women.

Adult↗
PubMed1981

Identification of hydrazone of norethindrone, a metabolic product resulting from the interaction between isoniazid and norethindrone.

Co-administration of isonicotinic acid hydrazide (isoniazid, INH) and 17 alpha-ethinyl-17 beta-hydroxyestr-4-en-3-one (norethindrone, NE) resulted in the formation of the isonicotinyl hydrazone of norethindrone (INH-NE) in rat stomach. Rat liver metabolized the latter compound in vitro. The metabolic product was characterized, following its derivatization with p-methoxy-benzaldehyde (PMBA), by comparison of chromatographic and mass spectral properties with synthetic reference compound. Results showed that INH-NE was cleaved at the amide bond resulting in the formation of the hydrazone of norethindrone. The physicochemical characteristics of synthetic PMBA hydrazone of norethindrone are described.

Animals↗
PubMed1982

Pharmacokinetics of norethindrone acetate in women after the insertion of a single subdermal implant releasing norethindrone acetate.

The metabolic clearance rate (MCR) of norethindrone acetate (NETA) and norethindrone (NET) levels in plasma were studied after an iv injection of [3H]NETA in three women before and at 1 week, 1, 2 and 6 months following the insertion of a single silastic subdermal implant releasing microquantities of NETA. No significant change in the MCR of NETA was observed at 1 week (459 +/- 72 1/day), 1 month (489 +/- 113 1/day) and 2 months (522 +/- 144 1/day) compared with that of control (525 +/- 108 1/day). However, MCR of NETA showed significant increase in women exposed to continuous presence of NETA for a period of 6 months (608 +/- 121 1/day; P less than 0.025). NETA was rapidly and extensively metabolized into NET. At 1 week, 1, 2 and 6 months of study, NET was observed to be present in higher amounts compared with NETA. The production rate (PR) of progesterone decreased significantly at 2 and 6 months of NETA implant insertion compared with the PR before the insertion of implant.

Adult↗
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↗
PubMed1991

Bioavailability of norethindrone and menstrual pattern after insertion of norethindrone acetate implants in rhesus monkeys.

Subdermal silastic implants releasing norethindrone acetate were inserted in five rhesus monkeys for a period of seven months. The serum norethindrone (NET) levels were estimated from blood samples collected fortnightly. There was an initial high level of NET followed by fluctuating levels of NET in 4 out of five monkeys. The serum NET values showed individual variation between time periods as well as between monkeys. The analysis of menstrual cycles showed initial amenorrhoea up to day 120-140 in four out of five monkeys. Only one monkey showed vaginal bleeding pattern comparable to normal menstrual cycles; this monkey had serum NET levels less than 10 ng/ml. The pharmacokinetic and pharmacodynamic parameters were similar to those reported in the human female.

Amenorrhea↗
PubMed1980

Bioavailability of norethindrone in rabbits after administration of norethindrone acetate in single, double and quadruple doses released through subcutaneous silastic implants.

Plasma level of norethindrone (NET) and in vivo release of norethindrone acetate (NETA) were studied in three groups of albino rabbits (5 animals/group) after insertion of one, two and four subcutaneous implants, each containing 40 mg crystalline NETA over a period of 24 weeks. The ratios of the in vivo release rate of steroid were 1, 1.9 and 3.9 in the animals of group I (one implant), group II (two implants) and group III (four implants) respectively. Thus, the in vivo release rate in group II and III showed an increase which was almost twice and four times as great as that of group I. However, the mean ratios of the serum NET levels were 1, 1.2 and 2.4 in animals of group I, II and III respectively. Thus, interestingly, the serum NET level did not show the expected twofold and fourfold increase and lacked correlation with the in vivo release. Although the insertion of multiple implants gives multiple increases in the in vivo steroid release, it does not give rise to a multiple increase in the serum levels of the steroid. It is possible that there is a kind of threshold of steroid concentration in the animals when they are loaded with exogenously administered steroid. When the steroid concentration tends to cross the threshold level, pharmacokinetic or pharmacodynamic processes of the animal work maximum to hold down the steroid level in blood plasma.

Animals↗
PubMed1979

Plasma levels of norethindrone and effect upon ovarian function during treatment with silastic implants containing norethindrone.

The study was made to evaluate the effect upon the ovarian steroid pattern during treatment with subcutaneously implanted silastic rods containing norethindrone. Four rods, each containing 37 mg norethindrone (NET), were implanted subcutaneously in five women and left in place for 135--200 days. Plasma levels of NET, estradiol and progesterone were determined by radioimmunoassays. After an initial peak found in all subjects, the plasma level of NET declined. Great day-to-day variations of NET were found. Ovulations were suppressed during treatment in three subjects. One subject had regular ovulations throughout treatment and in one subject a single ovulation was recorded. Peaks of estradiol without subsequent ovulation were found in two subjects. The bleeding pattern was irregular; three subjects had varying degrees of spotting and bleeding, two subjects were amenorrheic. The average daily release rate was 300/micrograms, calculated from the amount of steroids lost from the removed rods. This study indicates that the release of steroid from four NET rods is high enough only initially to completely inhibit ovulation.

Adult↗
PubMed1991

[Pharmacokinetics of norethindrone-3-oxime and norethindrone in rhesus monkeys].

After intravenous administration or nasal feeding of (6, 7-3H)-labelled norethindrone-3-oxime (NETO) or norethindrone (NET) to rhesus monkeys, the serum concentrations were determined by measuring the radioactivity after separation with HPLC. The serum concentrations of total extractable radioactivity were also measured without HPLC separation. In cases of nasal feeding, NETO and NET were quickly absorbed, and almost all of them were eliminated within 24 hours. NETO, when given via both routes, was partly metabolized to NET and partly remained in original form. The blood concentration--time curves for NETO and NET were adequately fitted to two compartment models. No significant difference in pharmacokinetic parameters between the two drugs was observed. The absolute bioavailability for NETO and NET were found to be 64.46 +/- 34.60% and 35.02 +/- 26.49% respectively.

Animals↗
PubMed1989

[Pharmacokinetics of norethindrone-oxime and norethindrone in rabbits after oral administration].

After oral administration of [3H]-labelled norethindrone-oxime (NETO) or norethindrone (NET) to rabbits, the blood concentrations of NETO and NET were determined by measuring the radioactivity after separation with HPLC. The pharmacokinetic parameters of the compounds were also compared. Experimental results indicate that both NETO and NET were quickly absorbed. Their elimination from blood revealed a fast and a slow phase. One portion of NETO was metabolized to NET, and the remainder was excreted in unchanged form. The amount of NETO and its metabolite, NET, in serum were about equal within 24 hours. The serum concentration-time curves of NETO and NET adequately fitted to a two-compartment model. There was significant difference between NETO and NET in Tmax (P less than 0.05). But no significant differences in other parameters (P greater than 0.05) were observed.

Administration, Oral↗
PubMedDate not supplied

Radioimmunoassay of norethindrone (17 alpha-ethynyl-17 beta-hydroxy-4-estren-3-one) and ethynyl-estradiol (17 alpha-ethynyl-1,3,5, (10)-estratien-3, 17 beta-diol). Application to human plasma determination of norethindrone after oral administration of this steroid.

The experiment conditions for the evaluation of Norethindrone (17 alpha-Ethynyl-17 beta-hydroxy-4-estren-3-one, NET) and Ethynyl-estradiol (17 alpha-ethynyl-1, 3, 5 (10) estratrien-3, 17 beta-diol, EE) by radioimmunoassay are described. A minimal quantity of 25 pg of these two steroids could be evaluated using different reduced metabolites of NET, very little cross reaction is observed with 200 pg of these metabolites. No effect was observed with estradiol for the EE-antiserum. The NET-antiserum was used to evaluate this steroid and ethynodiol diacetate after oral administration to female volunteers. Maximal values in the plasma (2-3% of the administered dose) was found between 1-3 h after administration and at 24 h a concentration of 0.1-0.3% still remained in the plasma.

Administration, Oral↗
PubMed1995

Serum norethindrone levels and menstrual pattern after the use of norethindrone implants in rhesus monkeys.

Subdermal Silastic implants releasing norethindrone (NET) were inserted in five rhesus monkeys for a period of seven months. The total length of the implants used was 160 mm (eight implants of 20 mm each) containing 160 mg of NET (1 mg NET/mm). The in vivo release rate of NET from the Silastic implants containing 160 mg NET was 3.12 micrograms/day/mm. Menstrual bleeding records were maintained and serum NET levels were estimated from blood samples collected during the period implants remained in situ. There was an initial rise in NET levels, followed by fluctuating levels of NET in three out of five monkeys. The menstrual cycle or bleeding episodes showed a pattern commensurate with the circulating NET levels. None of the monkeys showed intermenstrual bleeding during the treatment period. High levels of NET seem advantageous for an undisturbed menstrual cycle.

Animals↗
PubMed1979

Plasma levels of norethindrone after single oral dose administration of norethindrone and lynestrenol.

Single oral doses of 0.3 mg, 0.5 mg and 5 mg Norethindrone (NET) and 0.5 mg and 5 mg Lynestrenol (lyn) were given to five women. Lynestrenol is probably metabolized through NET and exerts its main biological activity as NET. Plasma concentrations of NET were determined by a radioimmunoassay at different intervals after administration of the tablets. Peak concentrations of NET were found within two hours after intake of each table. The plasma half life of Net after NET and lyn administration for the period 8-24 h was 8-11 h. No significant difference was found between the half life of NET and the NET tablets and after the lyn tablets. When 5 mg NET was given the plasma half life of NET for the period 24-72 h was around 10 h and this was significantly shorter than the half-life of NET after 5 mg lyn, which was 16 1/2 h. The systemic availability of the drugs was estimated by calculating and comparing the areas under the plasma concentration versus time curve (AUC). 0-24 H. The AUC 0.24 after 0.3 MG NET was almost identical to the AUC 0.24 after 0.5 mg lyn. The AUC 0-24 after 0.5 mg NET was significantly larger than after 0.5 lyn. No difference was found between the AUC 0-24 after 5 mg lyn and 5 mg NET. This study supports the concept of a conversion from lyn to NET. It also shows that there were only minor pharmacokinetic differences between the drugs when all samples were measured as NET.

Administration, Oral↗