Norethisterone

Endpoint summary

Description of key information

Norethisterone is a synthetic sex hormone and active ingredient of approved drugs since several decades. Norethisterone belongs to the category “steroidal progestins” and has progestogenic properties resembling those of the naturally occuring progesterone but is a more potent inhibitor of ovulation. Apart from the data on norethisterone, information from its ester derivates (norethisterone enanthate and acetate) can be used for characterization of the biological activity of progestin, because both esters are rapidly cleaved within the mammalian organism and thus, norethisterone is the systemically active metabolite irrespective of the form which is administered.

The clinical pharmacology and the absorption, distribution, metabolism and excretion of norethisterone and its ester derivates are well characterized as described in the current label of approved drugs.

 

Additional information

Summaries of the toxicokinetic properties of Norethisterone and its esters are taken from the Company Core Data Sheet (CCDS) [*] of each substance.

 

Absorption

Orally administered Norethisterone is rapidly and completely absorbed over a wide dose range. Peak serum concentrations of about 16 ng/ml are reached within about 1.5 hours of administration of one tablet Primolut N (5 mg). Due to a marked first-pass effect, the bioavailability of Norethisterone after an oral dose is about 64 %.

Orally administered Norethisterone acetate (NETA) is rapidly and completely absorbed over a wide dose range.Already during absorption and the first liver passage Norethisterone acetate is hydrolyzed to Norethisterone, the active drug substance, and acetic acid.Peak serum Norethisterone concentrations of about 18 ng/ml (after intake of 5 mg NETA) and 25 ng/ml (after intake of 10 mg NETA) are reached within about 2 hours of administration of one tablet Primolut Nor. Based on a relative bioavailability study, the drug is completely released from the tablet.

Norethisterone enantate was completely absorbed after intramuscular injection.The ester was quickly and eventually completely hydrolyzed to its pharmacologically active compound Norethisterone once it was released from the depot.Maximum levels of Norethisterone were measured about 3 - 10 days after i.m. administration. They amounted on average to 13.4 ± 5.4 ng/ml and 12.2 ± 2.7 ng/ml about 7 days (median) after i.m. administration of 200 mg Norethisterone enantate in 2 ml and 1 ml oily solution, respectively. Plasma levels of Norethisterone declined in two disposition phases with half-lives of 4 - 5 days and 15 - 20 days, respectively, which were due to a biphasic release of Norethisterone enantate from the depot.

Although there is no direct investigation on bioavailability of Norethisterone after i.m. administration of Norethisterone enantate reported, complete availability can be estimated by comparison of Norethisterone AUC values determined in different studies after i.v. injection of Norethisterone and after i.m. injection of Norethisterone enantate.

Concluding, the amount and rate of absorption has shown to be essentially the same for Norethisterone and Norethisterone acetate when comparing Cmax- and Tmax -values of the common active ingredient Norethisterone in serum following oral administration (about 16 ng/ml after intake of 5 mg Norethisterone, Cmax reached within about 1.5 hours; about 18 ng/ml after intake of 5 mg of Norethisterone acetate, Cmax reached within about 2 hours). For Norethisterone enantate data with oral administration is limited, since the drug has been using as depot drug. However, the prolonged depot-activity is merely achieved through the intramuscular application route and the choice of an oily formulation (e.g. castor oil – benzyl benzoate solution). The limited available information on absorption following oral ingestion for Norethisterone enantate (after oral administration more than half of the amount will be absorbed and eliminated within 24 hours) is not contradictive to the absorption characteristics of Norethisterone or Norethisterone acetate.

 

Distribution

Norethisterone is bound to serum albumin and to sex hormone binding globulin (SHBG). Only about 3-4 % of the total serum drug concentrations are present as free steroid, about 35 % and 61 % are bound to SHBG and albumin, respectively. The apparent volume of distribution of Norethisterone is 4.4 ± 1.3 L/kg. Following oral administration, the drug serum level time course follows a biphasic pattern. Both phases are characterized by half-lives of 1-2 and about 5-13 hours, respectively. Norethisterone is transferred into milk and the drug levels in breast milk were found to be about 10 % of those found in maternal plasma, irrespective of the route of administration. Based on a mean maximum drug level in maternal serum of about 16 ng/ml and an estimated daily intake of 600 ml of milk by the nursed infant, a maximum of about 1μg (0.02 % of the maternal dose) could reach the infant.

 

Metabolism

As pointed out above (cp. Absorption) the esters Norethisterone acetate and Norethisterone enantate are rapidly cleaved within mammalian organism to generate the systemically active ingredient Norethisterone following oral or intramuscular administration, respectively.

Norethisterone enantate is metabolized completely. Norethisterone enantate is split mainly in the liver by enzymatic hydrolysis into Norethisterone and heptanoic acid. While the fatty acid is metabolized by means of ß-oxidation, the released Norethisterone is transformed as exemplified below.

Norethisterone is mainly metabolized by saturation of the double bond in ring A of the steroid structure (reduction of the C4-C5 double bond) and the reduction of the 3-keto group to a hydroxyl group followed by conjugation to the corresponding sulfates and glucuronides. Some of these metabolites are eliminated rather slowly from plasma, with half-lives of about 67 hours. Therefore, during long-term treatment with daily oral administration of Norethisterone, some of these metabolites accumulate in the plasma.

The majority of metabolites found in urine were present as conjugates, mainly as sulfates, which are expected to be inactive.

Norethisterone is partly metabolized to ethinylestradiol after oral administration of Norethisterone or Norethisterone acetate in humans or after intramuscular administration of Norethisterone enantate in humans. The conversion results in an equivalent dose of about 4-6 µg ethinylestradiol per 1 mg orally administered Norethisterone / Norethisterone acetate. Based on these data systemic estrogen effects cannot be excluded.[**]

 

Excretion

Norethisterone is not excreted unchanged to a significant extent. Predominantly A-ring-reduced and hydroxylated metabolites as well as their conjugates (glucuronides and sulfates) are excreted via urine and feces in a ratio of about 7:3. The bulk of renally excreted metabolites was eliminated within 24 hours with a half-life of about 19 hours.

Regarding Norethisterone enantate (i.m. admin.), up to 85 % of the enantate dose was excreted within 30 days in urine (40 %) and feces (60 %). No unchanged Norethisterone enantate was recovered in urine or feces. In urine and feces, similar excretion half-lives of 6 - 9 days were estimated for radioactive labeled substances during the observation period of 30 days and - in a further study - an excretion half-life of 20 - 30 days was measured in urine between days 30 and 80 after i.m. administration of 200 mg ³H-Norethisterone enantate. Based on animal studies, retention of the drug in the body is not to be expected. 

 

Steady-state conditions

During multiple-dose daily administration with Norethisterone, an accumulation of the drug is unlikely because of the relatively short half-life of the drug. If, however, SHBG-inducing agents such as ethinylestradiol are co-administered, an increase in Norethisterone serum levels can occur because of the binding of Norethisterone to SHBG.

 

 

 

Additional data cited in RTECS/HSDB database (Jan 2010):

Adsorption/Distribution/Excretion

Norethisterone appears to bind to intestinal walls and are then slowly released into the bloodstream [1] In women given 15,16,3H- norethisterone acetate 20 muci IV in 10 % ethanol-water vehicle, norethisterone had biphasic disappearance with rapid initial disappearance in 1st 6 hr followed by slow disappearance phase (34.8 hr). Results are compared with other progestins data [2] In 25 BALB/c mice implanted subcutaneously with pellets containing 40% norethisterone and 60% cholesterol for 76-77 wk, absorption of norethisterone was estimated to be between 3.6 and 15.9 ug/day (mean, 7.7 ug/day).[3]

Rabbits excrete norethisterone metabolites predominantly in the urine ... while rats excrete them to 80% in bile [4] When 3H- or 14C-norethisterone was given orally to men, about half of the dose was excreted in the urine [5]

Although norethisterone is absorbed almost completely, it undergoes first-pass metabolism, which decreases its bioavailability to an average of 64%. There is wide inter individual variation in its absorption, which is estimated to be as high as three- to fivefold. Norethisterone is absorbed rapidly, achieving maximum serum concentrations within 1-4 hours. After doses of 0.5, 1 and 3 mg, the serum concentrations peaked at 2-5, 5-10 and up to 30 ng/ml, respectively.[6]

 

Metabolism

Metabolic removal of 17 alpha-ethynyl group from antifertility drug norethindrone, 17 alpha-ethynyl-17 -beta-hydroxyester-4 -en-3 -one affords ester-4 -ene-3,17 -dione. In earlier study, 17 alpha-ethynyl-5 alpha-19 -norandrostan-17 beta-ol-3 -one and 17 alpha-ethynyl-5 alpha-19 -norandrostan-3beta, 17 beta-diol were urinary metabolites [7]

After incubation of norethisterone with dog liver microsomes the 4beta,5beta-epoxide of norethisterone and a 6-oxygenated norethisterone derivative were obtained as minor metabolites [4]

Rabbit liver homogenates ... catalyze the deethinylation of norethisterone, giving rise to the metabolite oestr-4-ene-3,17-dione. [4]

When 3H- or 14C-norethisterone was given orally to men ...50-65% of the urinary radioactivity was sulfate conjugates. The major sulfate conjugate was that of 5beta-oestrane-3beta,17beta-diol; the major glucuronide conjugate was that of 5beta-oestrane-3alpha,17beta-diol. The other metabolites in the glucuronide and sulfate fraction were produced by reduction of norethisterone at C-3 and at the double-bond of ring A ... . Norethisterone is transformed by reductive enzymes to four isomeric ring-A-reduced (5alpha and 5beta) 3alpha- or 3beta-hydroxy metabolites ..[5]

 

The major metabolites of norethisterone are isomers of 5alpha-dihydronorethisterone and tetrahydronorethisterone, which are excreted largely as glucuronides. Because of steric hindrance of the bulky ethinyl group at position 17alpha, only a small percentage of norethisterone metabolites are conjugated at the 17beta-hydroxy group.The ethinyl group remains intact in 90% of metabolites.[6]

 

 

[1] The Chemical Society. Foreign Compound Metabolism in Mammals Volume 3.London: The Chemical Society, 1975., p. 166

[2] Singh H et al. AM J Obstet Gynecol 135(10) 409 (1979)

[3] IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT.(Multivolume work)., p. V21 452 (1979)

[4] IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT.(Multivolume work)., p. V21 453 (1979)

[5] IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT.(Multivolume work)., p. V21 454 (1979)

[6] IARC. Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to: World Health Organization, International Agency for Research on Cancer, 1972-PRESENT.(Multivolume work)., p. V72 232 (1999)

[7] The Chemical Society. Foreign Compound Metabolism in Mammals. Volume 1: A Review of the Literature Published Between 1960 and 1969.London: The Chemical Society, 1970., p. 244

[*]In accordance with ICH E2C(R1) and E2C(R2) recommendations a CCDS is to be prepared by the marketing authorisation holder for a medical product. It includes sections relating to safety, indications, dosing, pharmacology, and other information concerning the medicinal product. (cp. EMA Guidelines)

[**]A scheme of the metabolism of Norethisterone can be found here:https://www.ebi.ac.uk/chembl/compound_metabolism/CHEMBL1162[ChEMBL Database, EMBL's European Bioinformatics Institute, Cambridge , UK].