At least two functional auxiliaries are produced from norgestimate: norgestimate 3-oxime (reduced norgestimate; norelgestromin) and norelgestromin [1].

Absorption, Distribution and Excretion
The time to peak concentration (Tmax) of orally administered norethindrone is 0.5–2 hours. On day 21 of cycle 3, the peak plasma concentration (Cmax) of 17-deacetylenol was 1.82 ng/mL, with a Tmax of 1.5 hours and an area under the curve (AUC) of 16.1 h·ng/mL. Simultaneously, the peak plasma concentration (Cmax) of norethindrone was 2.79 ng/mL, with a Tmax of 1.7 hours and an AUC of 49.9 h·ng/mL. 45–49% of norethindrone is excreted in the urine and 16–49% in the feces. Unmetabolized norethindrone was not detected in urine. Data regarding the volume of distribution of norethindrone are not available. Data regarding the clearance of norethindrone are not available.
Absorption of norgestrol acetate (NGM) and ethinylestradiol (EE) is rapid after oral administration.
Peak serum concentrations of norgestrol acetate (NGMN) and ethinylestradiol (EE) are typically reached within 2 hours after administration of MonoNessa. Following multiple doses of 250 μg NGM/35 μg, the accumulation of NGMN and EE is approximately twice that of a single dose. The pharmacokinetics of NGMN are dose-proportional after administration of 180 μg to 250 μg NGM. Steady-state concentrations of NGMN and NG are reached on day 21. Due to the high affinity of norgestrol acetate for sex hormone-binding globulin (SHBG), its biological activity is limited, resulting in non-linear accumulation (approximately 8-fold). Both norgestrol acetate and NGMN have high binding rates to serum proteins (>97%). Norgestrol acetate binds to albumin but not to SHBG, while norgestrol acetate binds primarily to SHBG. Metabolites of norethindrone and ethinylestradiol are excreted via the kidneys and feces. Following administration of 14C-norethindrone, 47% (45-49%) and 37% (16-49%) of the radioactive material were excreted in urine and feces, respectively. Unmetabolized norethindrone was not detected in urine. Metabolites/Metabolites Norethindrone is rapidly deacetylated to active 17-deacetonogestrin, which is then deoxygenated to active norethindrone. 17-deacetonogestrin is primarily metabolized via CYP3A4 to a number of undefined hydroxylated metabolites, and secondarily via CYP2B6 and CYP2C9. Norethindrone is O-glucuronidated via UGT1A1 or oxidized via CYP3A4 to a number of undefined hydroxylated metabolites. Norgestimate undergoes rapid and complete first-pass metabolism (intestine and/or liver) to Norgestimate (NGMN) and norethindrone (NG), which are the major active metabolites of Norgestimate. Norgestimate undergoes extensive first-pass metabolism in the gastrointestinal tract and/or liver. The major active metabolite of Norgestimate is Norgestimate. Norgestimate is subsequently metabolized in the liver, with metabolites including the equally active norethindrone, as well as various hydroxylated and conjugated metabolites. In addition to 17-deacetylNorgestimate, several other Norgestimate metabolites have been identified in human urine following administration of radiolabeled Norgestimate. These metabolites include 18,19-dinor-17-pregnane-4-en-20-yn-3-one, 17-hydroxy-13-ethyl, (17α)-(-); 18,19-dinor-5β-17-pregnane-20-yn, 3α,17β-dihydroxy-13-ethyl, (17α), and various hydroxylated metabolites and conjugates of these metabolites. Limited metabolic information is available regarding levoNorgestimate, norethindrone, and structure-related contraceptive steroids. Both levoNorgestimate and norethindrone undergo extensive reduction of their α,β-unsaturated ketones on the A ring. LevoNorgestimate also undergoes hydroxylation at the carbon atoms at positions 2 and 16. Metabolites of both compounds primarily cycle as sulfates. In urine, levoNorgestimate metabolites are primarily found as glucuronides, while norethindrone metabolites are found as sulfates and glucuronides in roughly equal amounts. Among progestins with a structure associated with norethindrone, norethindrone acetate, ethinyl diacetate, norethindrone heptaate, and possibly norethindrone alcohol, are all rapidly hydrolyzed and converted into the parent compound and its metabolites. There is currently no conclusive evidence that norethindrone esters are converted into norethindrone. Among progestins with a structure associated with levoNorgestimate, desogestrel and pregnadienone do not appear to be converted into the parent compound. However, there is evidence that norethindrone ester can at least partially convert into levoNorgestimate. ...

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Biological Half-Life
Norethindrone ester undergoes rapid deacetylation. The half-life of the active metabolite of norethindrone ester, 17-deacetylonoephedrine, is 12–30 hours, while the half-life of norethindrone is 36.4 ± 10.2 hours.

Protein Binding
17-Desethindrone binds to albumin at a rate of 97.2%, while norethindrone binds to protein at a rate >97%, with 92.5% binding to sex hormone-binding globulin. Interactions Herbal products containing Hypericum perforatum may induce liver enzymes (cytochrome P450) and P-glycoprotein transporters, and may reduce the effectiveness of contraceptive steroids. This may also lead to breakthrough bleeding. Studies have shown that co-administration of lamotrigine with hormonal contraceptives significantly reduces plasma concentrations of lamotrigine due to the induction of glucuronidation. This may reduce the effectiveness of epilepsy control; therefore, dosage adjustment of lamotrigine may be necessary.

[1]. All progestins are not created equal. Steroids. 2003 Nov;68(10-13):879-90.

[2]. Preclinical evaluation of norgestimate, a progestin with minimal androgenic activity. Am J Obstet Gynecol. 1992 Oct;167(4 Pt 2):1191-6.

Norgestimate is a steroidal ester, ketooxime, and terminal alkyne compound. It is a contraceptive, progestin, and synthetic oral contraceptive. Norgestimate was first documented in 1977. Developed by Ortho Pharmaceuticals, it was intended to be a novel hormonal contraceptive with fewer side effects. It is typically formulated with ethinylestradiol as a combined oral contraceptive and can also be used to treat moderate acne vulgaris. Norgestimate was approved by the U.S. Food and Drug Administration (FDA) on December 29, 1989. Drug Indications Norgestimate is formulated with ethinylestradiol as a combined oral contraceptive. It can also be used in combination with low-dose ethinylestradiol for contraception and treatment of moderate acne vulgaris in women aged 15 and older. Mechanism of Action Progestin analogs such as Norgestimate reduce the frequency of hypothalamic gonadotropin-releasing hormone pulses, thereby reducing the levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These effects prevent ovulation. Norgestimate inhibits the hypothalamic-pituitary axis, reducing androgen synthesis. It can also induce the production of sex hormone-binding globulin, thereby reducing free testosterone levels. These effects collectively lead to a reduction in testosterone available to stimulate sebaceous glands, thus effectively treating certain types of acne. Combined oral contraceptives work by inhibiting gonadotropins. While their primary mechanism of action is ovulation inhibition, other changes include alterations in cervical mucus (increasing the difficulty for sperm to enter the uterus) and changes in the endometrium (reducing the likelihood of implantation). Receptor binding studies, as well as animal and human studies, have shown that norgestrol and its main serum metabolite, 17-deacetyloNorgestimate, have high progestin activity but very low intrinsic androgenic activity. When norgestrol is used in combination with ethinylestradiol, it does not counteract the estrogen-induced increase in sex hormone-binding globulin (SHBG), thus reducing serum testosterone levels. Progestins enter target cells via passive diffusion and bind to cytoplasmic (soluble) receptors that are loosely bound within the cell nucleus. Steroid receptor complexes initiate transcription, leading to increased protein synthesis. /Progestins/ Progestins can affect the serum concentrations of other hormones, especially estrogen. The effects of estrogen are regulated by progesterone, through mechanisms including reducing the availability or stability of hormone receptor complexes or shutting down specific hormone-responsive genes by direct interaction with progesterone receptors within the cell nucleus. Furthermore, estrogen pretreatment is crucial for enhancing the effects of progesterone, through mechanisms such as upregulating the number of progesterone receptors and/or increasing progesterone production, thereby creating a negative feedback mechanism that inhibits estrogen receptors. /Progestin/

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Therapeutic Use
Oral synthetic contraceptives; Norethindrone/analogs and derivatives
Norethindrone esters/ethinylestradiol are indicated for women who choose oral contraceptives as a method of contraception to prevent pregnancy. /US Product Label Contains/

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Drug Warnings
/Black Box Warning/ Warning: Smoking is associated with cardiovascular risk. Smoking increases the risk of serious cardiovascular events following the use of combined oral contraceptives. This risk increases with age, particularly in women over 35 years of age, and increases with the amount of smoking. Therefore, women over 35 years of age who smoke should not use combined oral contraceptives, including MonoNessa. Women with the following conditions should not use oral contraceptives: thrombophlebitis or thromboembolic disease; a history of deep vein thrombophlebitis or thromboembolic disease; cerebrovascular or coronary artery disease (current or past); valvular heart disease with complications; severe hypertension; diabetes with vascular involvement; headache with focal neurological symptoms; major surgery requiring prolonged bed rest; known or suspected breast cancer or a history of breast cancer; endometrial cancer or other known or suspected estrogen-dependent tumors; undiagnosed abnormal vaginal bleeding; cholestatic jaundice during pregnancy or jaundice caused by previous use of oral contraceptives; acute or chronic hepatocellular disease with abnormal liver function; hepatic adenoma or liver cancer; known or suspected pregnancy; allergy to any ingredient in this product. Taking oral contraceptives increases the risk of several serious illnesses, including myocardial infarction, thromboembolism, stroke, liver tumors, and gallbladder disease; however, the risk of serious illness or death is very small for healthy women without underlying risk factors. Morbidity and mortality are significantly increased if other underlying risk factors are present, such as hypertension, hyperlipidemia, obesity, and diabetes. Oral contraceptives have been shown to increase the relative and attributable risk of cerebrovascular events (thrombotic and hemorrhagic stroke), although overall, the risk is highest in older women (>35 years), those with hypertension, and smokers. Studies have found that hypertension is a risk factor for both types of stroke in users and non-users, and smoking interacts with hypertension, increasing the risk of stroke. In a large study, the relative risk of thrombotic stroke ranged from 3 in those with normal blood pressure to 14 in those with severe hypertension. The reported relative risk of hemorrhagic stroke in non-smokers taking oral contraceptives is 1.2, compared to 2.6 in smokers not taking oral contraceptives, 7.6 in smokers taking oral contraceptives, 1.8 in women with normal blood pressure, and 25.7 in women with severe hypertension. Attributable risk is also higher in older women.
For more complete data on drug warnings for nifedipine (44 total), please visit the HSDB record page.

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Pharmacodynamics
Nogestrol is a progestin used for contraception by inhibiting ovulation and for treating moderate acne vulgaris by lowering free testosterone levels. Its therapeutic index is wide due to the rarity of overdose. Patients should be informed of the risks of vascular problems, liver disease, high blood pressure, metabolic effects, headaches, and bleeding abnormalities.

C23H31NO3

369.4971

369.23

C, 74.76; H, 8.46; N, 3.79; O, 12.99

35189-28-7

Norgestimate-d6;1263194-12-2

6540478

White to off-white solid powder

1.2±0.1 g/cm3

497.9±45.0 °C at 760 mmHg

216ºC

254.9±28.7 °C

0.0±2.9 mmHg at 25°C

1.611

5

1

4

4

27

744

6

O(C(C([H])([H])[H])=O)[C@@]1(C#C[H])C([H])([H])C([H])([H])[C@@]2([H])[C@]3([H])C([H])([H])C([H])([H])C4=C([H])/C(/C([H])([H])C([H])([H])[C@]4([H])[C@@]3([H])C([H])([H])C([H])([H])[C@@]21C([H])([H])C([H])([H])[H])=N/O[H]

KIQQMECNKUGGKA-NMYWJIRASA-N

InChI=1S/C23H31NO3/c1-4-22-12-10-19-18-9-7-17(24-26)14-16(18)6-8-20(19)21(22)11-13-23(22,5-2)27-15(3)25/h2,14,18-21,26H,4,6-13H2,1,3H3/b24-17+/t18-,19+,20+,21-,22-,23-/m0/s1

[(3E,8R,9S,10R,13S,14S,17R)-13-ethyl-17-ethynyl-3-hydroxyimino-1,2,6,7,8,9,10,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-yl] acetate

Norgestimate; ORF-10131; D 138; AC-655; RWJ-10131; Dexnorgestrel acetime; Norgestrel oxime acetate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 74~125 mg/mL (200.3~338.3 mM)
Ethanol: ~4 mg/mL (~10.8 mM)

Solubility in Formulation 1: 2.08 mg/mL (5.63 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (5.63 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (5.63 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)