Absorption, Distribution and Excretion
Pharmacokinetic studies showed that chlormadinone acetate was rapidly and almost completely absorbed after oral administration, and bound to albumin rather than sex hormone-binding globulin (SHBG). Multiple-dose studies indicated that steady-state concentration was reached on day 7 after oral administration, with a peak plasma concentration of approximately 2 ng/mL. The half-life and metabolic clearance of chlormadinone acetate were calculated after a single intravenous injection of 60–90 μCi of 1-α-tritium-labeled chlormadinone acetate (specific activity 222 μCi/mg) into seven women aged 34–52 years. Plasma was extracted with acetone:methanol to determine total radioactivity; then extracted with water and ether to determine free steroid radioactivity; finally extracted with n-butanol to determine bound steroid radioactivity; and finally extracted with chloroform:methanol and separated by thin-layer chromatography with ether:benzene to determine the specific radioactivity of chlormadinone acetate. Blood samples were collected at 0.25, 0.5, 1, 8, and 24 hours, and every 24 hours thereafter, for 5 days. …All four curves (total radioactivity, bound steroids, free steroids, and specific radioactivity) exhibited the same biphasic pattern: a rapid decrease within approximately 24 hours, followed by equilibrium after 24 hours. The metabolic clearance was 42.61 L/day…These data estimate that the plasma concentration of chlormadinone in women taking 0.5 mg chlormadinone daily is approximately 0.45 ng/mL, which is about one-thirteenth of the progesterone concentration.
Published pharmacokinetic data for chlormadinone (CMA) are partially contradictory, especially regarding the terminal half-life (t(1/2,z)). Healthy female volunteers were given single and multiple doses of CMA (2 mg) and ethinyl estradiol (EE; 0.03 mg) over six menstrual cycles. Plasma concentrations of CMA and EE were determined by gas chromatography-mass spectrometry. Single-dose and steady-state pharmacokinetic parameters were calculated. In another study, healthy female volunteers received a single dose of 2 mg of radiolabeled CMA. The radioactivity concentration in fecal and urine samples was determined using liquid scintillation counting. Total radioactive excretion was calculated as a percentage of the administered dose. A total of 18 women completed the repeated-dose study. Peak plasma concentrations of CMA and EE were reached within 1 hour and 2 hours, respectively, after administration of the study drugs. The peak plasma concentration of CMA after a single dose was approximately 1600 pg/mL, and after multiple doses, it was approximately 2000 pg/mL. Over six cycles, both CMA and EE exhibited linear pharmacokinetic characteristics, with trough concentrations stabilizing at approximately 400–500 pg/mL and 20–40 pg/mL, respectively. The mass balance factor for CMA was 1.2–1.4, and for EE, it was 1.6–1.7; the cumulative factor for CMA was 1.7–2, and for EE, it was 1.7–1.8. The mean half-life of CMA after a single dose is approximately 25 hours, with a steady-state half-life of 36–39 hours. In excretion balance studies, the mean recovery rate of CMA was 87.3 ± 6.4%, with 45% excreted in urine and 42% in feces. The pharmacokinetics of CMA and EE were linear after multiple doses and remained stable during long-term administration after reaching steady state. The half-life of CMA after multiple doses is 36–39 hours, significantly shorter than the 80 hours commonly reported in the literature. This study investigated the bioavailability and bioequivalence of two film-coated tablets containing ethinyl estradiol and chlormadinone acetate (Bellissima as the investigational drug and the original drug as the reference drug) after a single oral dose in 20 healthy female volunteers. This study employed a single-center, randomized, single-dose, two-way crossover design with a 28-day washout period. Blood samples were collected within 168 hours after administration for pharmacokinetic analysis, and plasma concentrations of ethinylestradiol and chlormadinone were determined using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS). The observed mean maximum plasma concentrations (Cmax) of ethinylestradiol were 124.96 pg/mL (experimental group) and 129.12 pg/mL (control group). The mean Cmax of chlormadinone were 6.9566 ng/mL (experimental group) and 6.6663 ng/mL (control group). The geometric mean area under the plasma concentration-time curve (AUC(0-∞)) of ethinylestradiol were 1292.35 pg/mL·hr (experimental group) and 1380.49 pg/mL·hr (control group). The geometric mean AUC(0-∞) of chlormadinone acetate were 53.322 ng/mL·hr (experimental group) and 58.111 ng/mL·hr (control group). The median time to peak concentration (tmax) of ethinyl estradiol was 1.5 hours in both the experimental and control groups, while that of chlormedrone acetate was 1.0 hour in both groups. The plasma elimination half-life (t1/2) of ethinyl estradiol was 14.96 hours (experimental group) and 15.41 hours (reference group), respectively, while that of chlormedrone acetate was 56.63 hours (experimental group) and 56.17 hours (reference group), respectively. The primary target parameters AUC(0-∞) and Cmax were tested using analysis of variance (ANOVA). Point estimates of the AUC(0-∞) ratio and their 90% confidence intervals (experimental/reference group: 93.72% [86.62%-101.39%]) indicated a high degree of similarity between the two formulations in terms of ethinyl estradiol exposure. The Cmax of ethinyl estradiol also showed high similarity, with point estimates and 90% confidence intervals for the Cmax ratio of 96.18% (90.82%–101.86%). The point estimate for the AUC(0–∞) ratio of chlormadinone acetate was 91.60%, with 90% confidence intervals of 84.08%–99.79%. Furthermore, the point estimates and 90% confidence intervals for the Cmax of this active ingredient (104.72% [95.76%–114.53%]) also indicate interchangeability between the two formulations. Bioequivalence between the test and reference formulations has been confirmed, as the 90% confidence intervals for the AUC(0–∞) and Cmax of both ethinyl estradiol and chlormadinone acetate fall within the generally accepted 80%–125% range.
Following intravenous injection of radiolabeled chlormadinone acetate, the initial half-life of this steroid and its metabolites is short, at 2.4 hours, followed by a longer half-life of 80.1 hours. The mean metabolic clearance of chlormadinone acetate is 126 L/day, and the mean metabolic clearance of chlormadinone acetate and its metabolites is 42.6 L/day. The longer half-life and slower elimination rate are likely due to drug accumulation in adipose tissue.
Metabolism/Metabolites
The major metabolites of chlormadinone acetate are 2α-hydroxychlormadinone acetate and 3β-hydroxychlormadinone acetate. Incubation of chlormadinone acetate with human or rat liver microsomes primarily produces the 3β-hydroxy metabolite. Conversely, incubation with phenobarbital-treated rat liver microsomes produces the 2α-hydroxy metabolite, indicating that the metabolic pattern depends on the state of hepatic monooxygenases.

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Biological Half-Life
...The half-life of chlormadinone acetate (CMA) after a single dose is approximately 34 hours, and after multiple doses it is approximately 38 hours. ......
Published pharmacokinetic data for chlormadinone acetate (CMA) are partially contradictory, especially regarding the terminal half-life (t(1/2,z)). Healthy female volunteers underwent single and multiple doses of CMA (2 mg) and ethinyl estradiol (EE; 0.03 mg) over six menstrual cycles. After a single dose, the mean half-life of chlormadinone acetate was approximately 25 hours, with a steady-state half-life of 36–39 hours. After multiple doses, the half-life of chlormadinone acetate was 36–39 hours, significantly shorter than the commonly cited 80 hours in the literature.
The half-life and metabolic clearance of chlormadinone acetate were calculated after a single intravenous injection of 60 to 90 μCi of 1-α-tritium-labeled chlormadinone acetate (specific activity 222 μCi/mg) into seven women aged 34–52 years. Total radioactivity was determined by acetone:methanol extraction; free steroid radioactivity was determined by water and ether extraction; and bound steroid radioactivity was determined by n-butanol extraction. Specific radioactivity of chlormadinone acetate was determined by chloroform:methanol extraction followed by thin-layer chromatography with ether:benzene. Blood samples were collected at 0.25, 0.5, 1, 8, and 24 hours, and every 24 hours thereafter for 5 days. The mean radioactive half-life specifically identified as chlormadinone acetate was calculated using the TAIT and BURSTEIN methods to be 2.6 hours in the first 24 hours and 81.8 hours after 24 hours. ...
After intravenous injection of radiolabeled chlormadinone acetate, the initial half-life of this steroid and its metabolites was short, at 2.4 hours, followed by a longer half-life of 80.1 hours.

Non-Human Toxicity Values
Oral LD50 in rats: 6400 mg/kg body weight
Oral LD50 in mice: 6400 mg/kg body weight
Intraperitoneal LD50 in mice: 3 g/kg

Therapeutic Uses
Oral synthetic contraceptives; synthetic progestins. Chlormadinone acetate was discontinued in the United States in 1970, and the only product on the market at the time (an oral contraceptive) was withdrawn. Its use was also suspended in the United Kingdom that same year. Before the suspension, chlormadinone acetate was used as an oral contraceptive, either in combination with ethinylestradiol as a sequential contraceptive or as a progestin-only oral contraceptive. Chlormadinone acetate (usually used in combination with ethinylestradiol) was used to treat threatened miscarriage and dysmenorrhea. Ethinylestradiol/chlormadinone acetate 0.03/2 mg (EE/CMA) is a combined monophasic contraceptive with anti-androgenic properties. In a large, uncontrolled, multicenter trial (≤24 treatment cycles per woman) and two post-marketing surveillance studies (6 and 12 cycles), EE/CMA was shown to effectively prevent pregnancy. In a randomized, single-blind, multicenter trial, EE/CMA was significantly more effective than EE/levonorgestrel 0.03/0.15 mg/day in treating mild to moderate facial papulopustular acne and related conditions. EE/CMA was well-tolerated in both clinical trials and post-marketing surveillance studies. Adverse events were the same as those commonly associated with oral contraceptives. As expected, the most common menstrual irregularities were breakthrough bleeding, spotting, and amenorrhea.
This is an oral active progestin with anti-androgenic activity; it has been used in combination with other drugs as an oral contraceptive.
For more complete data on the therapeutic uses of chlormadinone acetate (out of 7), please visit the HSDB record page.

C23H29CLO4

404.93

404.175

302-22-7

Chlormadinone acetate-d6-1;Chlormadinone acetate-d3

9324

Light yellow to yellow solid powder

1.2±0.1 g/cm3

512.5±50.0 °C at 760 mmHg

212ºC

172.5±29.1 °C

0.0±1.3 mmHg at 25°C

1.563

3.42

0

4

3

28

827

6

CC(=O)[C@]1(CC[C@@H]2[C@@]1(CC[C@H]3[C@H]2C=C(C4=CC(=O)CC[C@]34C)Cl)C)OC(=O)C

QMBJSIBWORFWQT-DFXBJWIESA-N

InChI=1S/C23H29ClO4/c1-13(25)23(28-14(2)26)10-7-18-16-12-20(24)19-11-15(27)5-8-21(19,3)17(16)6-9-22(18,23)4/h11-12,16-18H,5-10H2,1-4H3/t16-,17+,18+,21-,22+,23+/m1/s1

[(8R,9S,10R,13S,14S,17R)-17-acetyl-6-chloro-10,13-dimethyl-3-oxo-2,8,9,11,12,14,15,16-octahydro-1H-cyclopenta[a]phenanthren-17-yl] acetate

Ay 13390 6; Ay133906; Ay-13390-6

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 : ~10 mg/mL (~24.70 mM)
H2O : < 0.1 mg/mL

Solubility in Formulation 1: ≥ 1 mg/mL (2.47 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 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of 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: ≥ 1 mg/mL (2.47 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 10.0 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: ≥ 1 mg/mL (2.47 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 10.0 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.)