progestogen Receptor

The toxic effects of drospirenone (10-150 μM, 24-48 h) on PLHC-1 cells had effective concentration limits (EC50 values) of 105-119 μM for 24 hours and 51-58 μM for 48 hours [1]. Drospirenone (0.01-10 µM, 24 h) inhibits PAI-1 and tPA in HEEC aqueous solutions [2]. Cellular ROS generation in PLHC-1 at -200 µM for 15-120 min [2]. Addition of 100 µM, 72 h) to the mouse model S9 component can damage DNA in MCF-7 cells [3].

In both male and female mice, oral dospirenone (10–100 mg/kg) for five days damages the DNA in the bone marrow cells [3].

Cytotoxicity assay [1]
Cell Types: PLHC-1 Cell
Tested Concentrations: 10-150 µM
Incubation Duration: 24 hrs (hours), 48 hrs (hours)
Experimental Results: Cell viability diminished by 50%, effective concentration after 24 hrs (hours) was 102-119μM, effective after 48 hrs (hours) The concentration is 51-58μM.

Animal/Disease Models: Adult female mice [3]
Doses: 10 mg/kg, 100mg/kg
Route of Administration: po (oral gavage)
Experimental Results: DNA damage was induced at dose rates of 10 and 100 mg/kg. Concomitant use with ethinyl estradiol enhances genotoxicity.

Absorption, Distribution and Excretion
Due to the first-pass effect, the absolute bioavailability of drospirenone is approximately 76%. Peak plasma concentrations are reached within 1 to 2 hours after oral administration, estimated to be 60 to 87 ng/mL. A European monograph on estradiol and drospirenone combination formulations indicates that drospirenone is rapidly and completely absorbed. This monograph reports that Cmax is reached approximately 1 hour after administration, at 21.9 ng/mL. Absolute bioavailability is reported to range from 76% to 85%. Multiple metabolites of drospirenone are detectable in urine and feces. Approximately 10 days after administration, drospirenone is almost completely eliminated from the body, at which point unchanged drospirenone is undetectable in urine and feces. Of the metabolites detected in urine, 38% to 47% are present as glucuronide and sulfate conjugates. In feces, approximately 17% to 20% of the identifiable metabolites are excreted as glucuronide and sulfate conjugates.
According to the FDA labeling of Yaz (Yasmin), the estimated volume of distribution (VOD) of drospirenone is 4 L/kg. Prescription information for estradiol and drospirenone combination formulations estimates the VOD to be 3.7–4.2 L/kg.
Drospirenone is rapidly cleared, typically within 2–3 days after the last active tablet. Serum clearance of drospirenone is calculated to be 1.2–1.5 ml/min/kg, but this value may vary from patient to patient, reaching up to 25%. The absolute bioavailability of a single drospirenone tablet (DRSP) is approximately 76%. After administration of Gianvi, serum concentrations of DRSP and EE reach peak levels within 1–2 hours. Following a single dose of 1–10 mg, the pharmacokinetics of DRSP are dose-proportional. Steady-state DRSP concentrations are observed after 8 days of daily Gianvi administration. Following multiple doses of Gianvi, serum Cmax and AUC (0-24 hours) values of DRSP increased approximately 2 to 3 times. Under dietary (high-fat meal) conditions, after a single dose of a Gianvi-like formulation, the absorption rate of DRSP and EE was slower, with serum Cmax of both components decreasing by approximately 40%. However, the extent of DRSP absorption remained unchanged. Serum levels of DRSP and EE decreased in two phases. The apparent volume of distribution of DRSP is approximately 4 L/kg, and the apparent volume of distribution of EE has been reported to be approximately 4-5 L/kg. For more complete data on the absorption, distribution, and excretion of drospirenone (10 in total), please visit the HSDB record page.

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Metabolism/Metabolites
Drospirenone is extensively metabolized. The two major inactive metabolites identified are the acidic form (M11) resulting from the ring-opening of the drospirenone lactone ring and 4,5-dihydrodrospirenone-3-sulfate (M14). Drospironone can also be oxidatively metabolized by the hepatic cytochrome P450 enzyme CYP3A4. The two major metabolites of drospironone (DRSP) found in human plasma are the acidic form resulting from the ring-opening of the drospironone lactone ring and 4,5-dihydrodrospironone-3-sulfate. These metabolites have been shown to be pharmacologically inactive. In in vitro studies using human liver microsomes, drospironone was metabolized only in small amounts, primarily via cytochrome P450 3A4 (CYP3A4). The serum half-life of drospironone is estimated to be 30 hours. The excretion half-life of drospironone metabolites in urine and feces is approximately 40 hours. The final disposal phase half-life of DRSP serum levels after single and multiple dosing regimens is approximately 30 hours.

Protein Binding
Drospirenone binds to approximately 95% to 97% of serum plasma proteins, primarily albumin. In vitro studies have shown that drospirenone has a low affinity for sex hormone-binding globulin (SHBG). Other literature indicates that drospirenone can bind to serum albumin, but not to SHBG or corticosteroid-binding globulin (CBG). Only 3% to 5% of drospirenone exists in its free steroid form.

[1]. Drospirenone induces the accumulation of triacylglycerides in the fish hepatoma cell line, PLHC-1 . Science of The Total Environment, 2019, 692: 653-659.

[2]. Drospirenone effects on the plasminogen activator system in immortalized human endometrial endothelial cells . Reproductive sciences, 2021, 28: 1974-1980.

[3]. Genotoxic effects of drospirenone and ethinylestradiol in human breast cells (in vitro) and bone marrow cells of female mice (in vivo) . Drug and Chemical Toxicology, 2022, 45(4): 1493-1499.

[4]. Drospirenone for oral contraception and hormone replacement therapy: are its cardiovascular risks and benefits the same as other progestogens? . Drugs, 2007, 67: 647-655.

[5]. The novel progestin drospirenone and its natural counterpart progesterone: biochemical profile and antiandrogenic potential. Contraception, 1996. 54(4): p. 243-51.

[6]. Drospirenone: a novel progestogen with antimineralocorticoid and antiandrogenic activity. Pharmacological characterization in animal models. Contraception, 1995. 51(2): p. 99-110.

[7]. Safety and efficacy of drospirenone used in a continuous combination with 17beta-estradiol for prevention of postmenopausal osteoporosis. Climacteric, 2004. 7(1): p. 103-11.

Drospironone is a steroidal lactone and a 3-oxo-Δ⁴ steroid compound. It has multiple uses, including contraception, aldosterone antagonism, and progestin. Drospironone is a synthetic progestin commonly found in the popular oral contraceptive Yaz, usually used in combination with ethinylestradiol. Recently, Health Canada and the U.S. Food and Drug Administration (FDA) approved its use in combination with estradiol for oral contraception. In addition to contraception, drospironone is also used in combination with estrogen to treat acne and premenstrual syndrome (PMDD). Due to the potential increase in the risk of venous thromboembolism associated with drospironone use, its safety has been a subject of considerable concern. However, a 2012 safety statement from the FDA indicated that the extent to which drospironone use increases the risk of thromboembolic events was unclear, as related research results were conflicting. Some studies showed a significant increase in risk, while others indicated no risk of thromboembolic events. The FDA stated that taking oral contraceptives such as drospirenone increases the risk of venous thromboembolism, but this risk is lower than the risk of developing the condition during pregnancy and postpartum, and this should be considered when assessing the potential risks of hormonal contraceptives. Drspirenone is a progestin. There are reports of drospirenone in cynomolgus monkeys, and relevant data are available. Drspirenone is a synthetic spironolactone analog and a progestin with both progestin and anti-mineralocorticoid activity. Drspirenone binds to the progesterone receptor, and the resulting complex is activated and binds to specific sites on DNA. This leads to inhibition of luteinizing hormone (LH) activity, suppression of ovulation, and changes in cervical mucus and the endometrium. This makes it more difficult for sperm to enter the uterus and implant. This drug is used in oral contraceptives. See also: drospirenone; estradiol (ingredient); drospirenone; estradiol (ingredient)... See more...

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Drug Indications
Drospirenone, used in combination with ethinylestradiol or estradiol, is an oral contraceptive for the prevention of pregnancy. In addition to its contraceptive effect, this combination is also used to treat symptoms of moderate acne vulgaris and premenstrual anxiety. This drug is approved for use in combination with estrogen to treat menopausal symptoms such as vasomotor symptoms and vulvovaginal atrophy. The use of drospirenone in combination with estrogen also helps prevent osteoporosis in women who have been postmenopausal for at least one year and are not suitable for other therapies. Sometimes, drospirenone appears in formulations containing estrogen and folic acid for folic acid supplementation during oral contraception. When used to treat acne vulgaris, drospirenone-containing contraceptives are only indicated for women aged 14 years and older who have started menstruating, wish to use oral contraception, and have no contraindications to oral contraception. Uses outside the indications for this drug include the treatment of menstrual irregularities, dysmenorrhea, hirsutism, and endometriosis.
FDA Label
Treatment of Endometriosis
Prevention of Pregnancy
Mechanism of Action
Drospirenone and ethinylestradiol, when used together, inhibit the release of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), thereby preventing ovulation. Other changes caused by this drug that may help prevent pregnancy include altering the consistency of cervical mucus, hindering sperm motility, and reducing the chances of embryo implantation. Drrospirenone is an analogue of the diuretic spironolactone and has anti-mineralocorticoid activity, blocking aldosterone receptors to increase sodium and water excretion. Animal studies have shown that drospirenone produces anti-androgenic activity. This activity helps antagonize the effects of natural androgens, inhibiting the binding of dihydrotestosterone (DHT) to its receptors and preventing androgen synthesis in the ovaries, thus helping to treat acne and hirsutism. Drrospirenone can also reduce the degree of edema in sebaceous gland follicles during the second half of the menstrual cycle (when acne often occurs).
Combined oral contraceptives (COCs) work by inhibiting gonadotropins. While their primary mechanism of action is ovulation inhibition, other alterations include changes in cervical mucus (increasing the difficulty for sperm to enter the uterus) and the endometrium (reducing the likelihood of implantation).
Drospirenone is a spironolactone analog with anti-mineralocorticoid activity. Animal and in vitro preclinical studies have shown that drospirenone does not possess androgenic, estrogenic, glucocorticoid, or anti-glucocorticoid activity. Preclinical animal studies have also shown that drospirenone has anti-androgenic activity.
Acne vulgaris is a skin condition with complex etiologies, including androgen-induced sebum secretion. Although the combined use of ethinylestradiol and drospirenone increases sex hormone-binding globulin (SHBG) levels and decreases free testosterone levels, the relationship between these changes and the reduction in the severity of facial acne in healthy women is unclear. The effect of drospirenone's anti-androgenic activity on acne is also unknown.
…The pharmacological properties of drospirenone were investigated in vitro and in vivo in suitable animal models by receptor binding and transcriptional activation assays. Consistent with the qualitative analysis of progesterone, this compound exhibits strong binding affinity to progesterone and mineralocorticoid receptors, but lower affinity for androgen and glucocorticoid receptors. No binding to estrogen receptors was detected. The steroid hormone agonist and antagonist activities of progesterone and drospirenone were compared in transcriptional activation assays. Single steroid hormone receptors were artificially co-expressed with reporter genes in suitable cell lines. Neither hormone induced any androgen receptor-mediated agonist activity. Conversely, both progesterone and drospirenone significantly antagonized androgen-stimulated transcriptional activation. Similarly, both compounds showed weak activation of mineralocorticoid receptors but exhibited potent aldosterone antagonist activity. Drspirenone did not induce glucocorticoid receptor-driven transcriptional activation. Progesterone is a weak agonist in this respect. Drspirenone, with potent progestin and anti-gonadotropic activity, has been studied in various animal models. It effectively promotes pregnancy maintenance in ovariectomized rats, inhibits ovulation in rats and mice, and stimulates endometrial transformation in rabbits. Furthermore, drospirenone exhibits potent anti-gonadotropic activity in male cynomolgus monkeys, specifically reducing testosterone levels. The progestin potency of drospirenone is comparable to that of norethindrone acetate. Most clinically used progestins possess androgenic activity. Like progesterone, drospirenone does not possess androgenic activity but rather exhibits anti-androgenic effects. This property has been demonstrated in castrated male rats replaced with testosterone propionate, manifesting as dose-dependent inhibition of accessory organ (seminal vesicle, prostate) growth. In this model, the potency of drospirenone is approximately one-third that of cyproterone acetate. Like progesterone, drospirenone possesses anti-mineralocorticoid activity, leading to a moderate increase in sodium and water excretion. This is a remarkable property not previously described in any other synthetic progestin. The potency of drospirenone in this respect is eight to ten times that of spironolactone. Natriuretic effects were observed in rats administered drospirenone daily at a dose of 10 mg/rat for at least three weeks. Drspirenone does not possess any estrogenic, glucocorticoid, or anti-glucocorticoid activity. In summary, drospirenone, like progesterone, possesses potent progestin, anti-mineralocorticoid, and anti-androgenic activities within a similar dose range. For more complete data on the mechanisms of action of drospirenone (9 in total), please visit the HSDB record page.

C24H30O3

366.49

366.219

C, 78.65; H, 8.25; O, 13.10

67392-87-4

Drospirenone-d4;2376035-94-6;Drospirenone-d4-1

68873

White to off-white solid powder

1.3±0.1 g/cm3

552.2±50.0 °C at 760 mmHg

196-200ºC

241.6±30.2 °C

0.0±1.5 mmHg at 25°C

1.610

3.15

0

3

0

27

828

10

O1C(C([H])([H])C([H])([H])[C@@]21[C@@]1(C([H])([H])[H])C([H])([H])C([H])([H])[C@]3([H])[C@@]4(C([H])([H])[H])C([H])([H])C([H])([H])C(C([H])=C4[C@]4([H])C([H])([H])[C@]4([H])[C@@]3([H])[C@]1([H])[C@]1([H])C([H])([H])[C@@]12[H])=O)=O

METQSPRSQINEEU-HXCATZOESA-N

InChI=1S/C24H30O3/c1-22-6-3-12(25)9-17(22)13-10-14(13)20-16(22)4-7-23(2)21(20)15-11-18(15)24(23)8-5-19(26)27-24/h9,13-16,18,20-21H,3-8,10-11H2,1-2H3/t13-,14+,15-,16+,18+,20-,21+,22-,23+,24+/m1/s1

(1R,2R,4R,10R,11S,14S,15S,16S,18S,19S)-10,14-dimethylspiro[hexacyclo[9.8.0.02,4.05,10.014,19.016,18]nonadec-5-ene-15,5'-oxolane]-2',7-dione

Drospirenona; Drospirenone; Dehydrospirorenone; dihydrospirorenone; drospirenone; Drospirenonum; ZK 3059; ZK30595

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO: 50~73 mg/mL (136.4~199.2 mM)
Ethanol: ~12 mg/mL (~32.7 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (6.82 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 25.0 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: ≥ 2.5 mg/mL (6.82 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 25.0 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: ≥ 2.5 mg/mL (6.82 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 25.0 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.)