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
The absolute bioavailability of drospirenone is approximately 76% due to first-pass effects. The maximum plasma concentration of drospirenone occurs within 1 to 2 hours after oral administration and is estimated to range between 60 and 87 ng/mL. A European prescribing monograph for the combination product of estradiol and drospirenone indicates that drospirenone is both completely and rapidly absorbed. It reports a Cmax of 21.9 ng/ml, achieved approximately 1-hour post-administration. The absolute bioavailability is reported to range between 76 to 85%.
Various metabolites of drospirenone are measured in the urine and feces. Drospirenone elimination from the body is almost after 10 days post-administration when negligible amounts of drospirenone are found unchanged in both the urine and feces. Between 38% to 47% of the metabolites are identified as glucuronide and sulfate conjugates in the urine. In the feces, approximately 17% to 20% of identifiable metabolites are found to be excreted as glucuronides and sulfates.
The volume of distribution of drospirenone is estimated to be 4 L/kg, according to the FDA label for Yaz. Prescribing information from a combination of estradiol and drospirenone estimates the volume of distribution to range from 3.7- 4.2 L/kg.
Drospirenone is rapidly cleared, typically within 2-3 days of administration of the last active tablet. The rate of clearance of drospirenone calculated in the serum ranges from 1.2-1.5 ml/min/kg, however, this value can vary by up to 25% according to the patient.
The absolute bioavailability of drospirenone (DRSP) from a single entity tablet is about 76%. Serum concentrations of DRSP and EE reached peak levels within 1-2 hours after administration of Gianvi.
The pharmacokinetics of DRSP are dose proportional following single doses ranging from 1-10 mg. Following daily dosing of Gianvi, steady state DRSP concentrations were observed after 8 days. There was about 2 to 3 fold accumulation in serum Cmax and AUC (0-24hr) values of DRSP following multiple dose administration of Gianvi.
The rate of absorption of DRSP and EE following single administration of a formulation similar to Gianvi was slower under fed (high fat meal) conditions with the serum Cmax being reduced about 40% for both components. The extent of absorption of DRSP, however, remained unchanged.
DRSP and EE serum levels decline in two phases. The apparent volume of distribution of DRSP is approximately 4 L/kg and that of EE is reported to be approximately 4-5 L/kg.
For more Absorption, Distribution and Excretion (Complete) data for Drospirenone (10 total), please visit the HSDB record page.

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Metabolism / Metabolites
Drospirenone is heavily metabolized. The two major inactive metabolites identified are the acid form of drospirenone produced by the opening of its lactone ring, known as M11, and the 4,5-dihydro-drospirenone-3-sulfate (M14). Drospirenone also undergoes oxidative metabolism via the hepatic cytochrome enzyme CYP3A4.
The two main metabolites of DRSP found in human plasma were identified to be the acid form of DRSP generated by opening of the lactone ring and the 4,5-dihydrodrospirenone-3-sulfate. These metabolites were shown not to be pharmacologically active. In in vitro studies with human liver microsomes, DRSP was metabolized only to a minor extent mainly by Cytochrome P450 3A4 (CYP3A4).

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Biological Half-Life
The serum half-life of drospirenone is estimated to be 30 hours. The half-life of drospirenone metabolite excretion in the urine and feces is approximately 40 hours.
DRSP serum levels are characterized by a terminal disposition phase half-life of approximately 30 hours after both single and multiple dose regimens.

Protein Binding
Drospirenone is about 95% to 97% bound to serum plasma protein, likely to albumin. During in vitro studies, drospirenone was found to bind with low affinity to sex hormone-binding globulin (SHBG). Another reference indicates that drospirenone binds to serum albumin but does not bind to sex hormone-binding globulin (SHBG), nor corticoid binding globulin (CBG). Only 3-5% of the total drospirenone concentration is measured as a free steroid.

[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.

Drospirenone is a steroid lactone and a 3-oxo-Delta(4) steroid. It has a role as a contraceptive drug, an aldosterone antagonist and a progestin.
Drospirenone is a synthetic progestin commonly found in the popular oral contraceptive, Yaz in combination with [Ethinyl estradiol]. Most recently, it was approved by both Health Canada and the FDA in combination with [Estetrol] as an oral contraceptive therapy. Aside from its contraceptive effects, drospirenone is used with estrogens to control acne and premenstrual dysphoric disorder (PMDD). Drospirenone has been the subject of widespread safety concern due to the possibility of an increased risk of venous thromboembolism associated with its use. In 2012, however, a safety statement by the FDA concluded that the increase in the risk of thromboembolism resulting from the use of drospirenone remains unclear, as studies regarding this risk are conflicting. Some studies have demonstrated a significantly increased risk and some demonstrating no risk of thromboembolic events. In its statement, the FDA has mentioned that increased risk of venous thromboembolism with oral contraceptives such as drospirenone exists but remains lower than the risk of this condition during pregnancy and during the postpartum period, and this should be considered when assessing potential risks of hormonal contraceptive use.
Drospirenone is a Progestin.
Drospirenone has been reported in Macaca fascicularis with data available.
Drospirenone is a synthetic spironolactone analogue and progestin with progestational and anti-mineralocorticoid activity. Drospirenone binds to the progesterone receptor, the resulting complex becomes activated and binds to specific sites on DNA. This results in a suppression of LH activity and an inhibition of ovulation as well as an alteration in the cervical mucus and endometrium. This leads to an increased difficulty of sperm entry into the uterus and implantation. This drug is used in oral contraceptives.
See also: Drospirenone; estradiol (component of); Drospirenone; estetrol (component of) ... View More ...

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Drug Indication
Drospirenone, in combination with ethinyl estradiol or estetrol, is indicated as an oral contraceptive for the prevention of pregnancy. In addition to its use for contraceptive effects, this combination is used to treat moderate acne vulgaris and the symptoms of premenstrual dysphoric disorder. The drug has approved indications for combination with estrogens for the treatment of menopause-associated symptoms, such as vasomotor symptoms and vulvovaginal atrophy. Drospirenone combined with estrogen may also may aid in the prevention of osteoporosis in women who have been post-menopausal for at least a year and are not candidates for other therapies. It can sometimes be found in preparations containing estrogen and folic acid for folic acid replenishment during oral contraception. When used for the treatment of acne vulgaris, drospirenone-containing contraceptives should only be used in women ≥14 years of age who have experienced menarche, desire oral contraception, and do not have any contraindications to oral contraceptives. Off-label uses for this drug include the treatment of menstrual irregularities, dysmenorrhea, hirsutism, and endometriosis.
FDA Label
Treatment of endometriosis
Prevention of pregnancy

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Mechanism of Action
Drospirenone and ethinyl estradiol in combination suppress the release of follicle stimulating hormone (FSH) and luteinizing hormone (LH), preventing ovulation. Other changes induced by this drug which may aid in the prevention of pregnancy include alterations in cervical mucus consistency, hindering sperm movement, and lowering the chance of embryo implantation. Drospirenone is an analog of the diuretic spironolactone, which exerts anti-mineralocorticoid activity, blocking aldosterone receptors, which increases sodium and water excretion. Studies in animals have demonstrated that drospirenone administration leads to antiandrogenic activity. This activity helps to oppose the effects of naturally occurring androgens, inhibiting the binding of dihydrotestosterone (DHT) to its receptor, and preventing androgen synthesis in the ovaries, helping to treat acne and hirsutism. Drospirenone may also decrease the level of edema in sebaceous follicle during the second half of the menstrual cycle, when acne often appears.
Combination oral contraceptives (COCs) act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increases the difficulty of sperm entry into the uterus) and the endometrium (which reduces the likelihood of implantation).
Drospirenone is a spironolactone analogue with antimineralocorticoid activity. Preclinical studies in animals and in vitro have shown that drospirenone has no androgenic, estrogenic, glucocorticoid, or antiglucocorticoid activity. Preclinical studies in animals have also shown that drospirenone has antiandrogenic activity.
Acne vulgaris is a skin condition with a multifactorial etiology including androgen stimulation of sebum production. While the combination of ethinyl estradiol and drospirenone increases sex hormone binding globulin (SHBG) and decreases free testosterone, the relationship between these changes and a decrease in the severity of facial acne in otherwise healthy women with this skin condition has not been established. The impact of the antiandrogenic activity of drospirenone on acne is not known.
.... The pharmacological properties of drospirenone were investigated in vitro by receptor binding and transactivation experiments and in vivo in appropriate animal models. In qualitative agreement with progesterone, the compound binds strongly to the progesterone and the mineralocorticoid receptor and with lower affinity to androgen and glucocorticoid receptors. There is no detectable binding to the estrogen receptor. Steroid hormone agonistic and antagonistic activities of progesterone and drospirenone were compared in transactivation experiments. Individual steroid hormone receptors were artificially expressed together with a reporter gene in appropriate cell lines. Both hormones were unable to induce any androgen receptor-mediated agonistic activity. Rather, both progesterone and drospirenone distinctly antagonized androgen-stimulated transcriptional activation. Likewise, both compounds only very weakly activated the mineralocorticoid receptor but showed potent aldosterone antagonistic activity. Drospirenone did not induce glucocorticoid receptor-driven transactivation. Progesterone was a weak agonist in this respect. Drospirenone exerts potent progestogenic and antigonadotropic activity which was studied in various animal species. It efficiently promotes the maintenance of pregnancy in ovariectomized rats, inhibits ovulation in rats and mice and stimulates endometrial transformation in the rabbit. Furthermore, drospirenone shows potent antigonadotropic, i.e., testosterone-lowering activity in male cynomolgus monkeys. The progestogenic potency of drospirenone was found to be in the range of that of norethisterone acetate. The majority of clinically used progestogens are androgenic. Drospirenone, like progesterone, has no androgenic but rather an antiandrogenic effect. This property was demonstrated in castrated, testosterone propionate substituted male rats by a dose-dependent inhibition of accessory sex organ growth (seminal vesicles, prostate). In this model, the potency of drospirenone was about a third that of cyproterone acetate. Drospirenone, like progesterone, shows antimineralocorticoid activity, which causes moderately increased sodium and water excretion. This is an outstanding characteristic which has not been described for any other synthetic progestogen before. Drospirenone is eight to ten times more effective in this respect than spironolactone. The natriuretic effect was demonstrable for at least three weeks upon daily treatment of rats with a dose of 10 mg/animal. Drospirenone is devoid of any estrogenic, glucocorticoid or antiglucocorticoid activity. In summary, drospirenone, like progesterone, combines potent progestogenic with antimineralocorticoid and antiandrogenic activity in a similar dose range.
For more Mechanism of Action (Complete) data for Drospirenone (9 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.)