Absorption, Distribution and Excretion
... Pharmacokinetic studies have shown rapid and almost complete absorption after oral administration, and chlormadinone acetate is being bound to albumin rather than SHBG (Sex-Hormone-Binding-Globulin). Multiple dosing studies have demonstrated that steady state is reached by day 7 after oral administration with peak plasma concentrations in the region of 2 ng/mL. ...
The half-life and metabolic clearance rate of chlormadinone acetate were computed after a single iv injection of 60 to 90 mcCi 1-alpha-tritiated-chlormadinone acetate (specific activity 222 mcCi/mg) into 7 women aged 34-52 years. Plasma was extracted with acetone:MeOH for total radioactivity; then extracted with water and ether for free steroid radioactivity; then with n-butanol for conjugated steroid radioactivity; and finally extracted with chloroform:MeOH and chromatographed on thin layer with ether:benzene for specific radioactivity due to chlormadinone acetate. Blood samples were taken at 0 .25, 0.5, 1, 8, 24 hours and every 24 hours for 5 days. ... All 4 curves, total radioactivity, conjugated steroids, free steroids, and specific activity had the same biphasic form: a rapid loss for about 24 hours, and an approaching equilibrium after 24 hours. The metabolic clearance rate was 42.61 liters per day... These data generate an estimate of the concentration of chlormadinone acetate in plasma of women taking 0.5 mg daily: about .45 ng/mL, i.e. about one-thirteenth the concentration of progesterone.
Published data on pharmacokinetic parameters for chlormadinone acetate (CMA) are in part contradictory, especially with regard to terminal half-life (t(1/2,z)). Single and multiple doses of CMA (2 mg) and ethinylestradiol (EE; 0.03 mg) were administered to healthy female volunteers for 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 a separate study, healthy female volunteers were given a single 2-mg dose of radiolabeled CMA. Concentrations of radioactivity in fecal and urine samples were determined via liquid scintillation. Excretion of total radioactivity was calculated as percentage of administered dose. Eighteen women completed the repeated-dose study. Peak plasma concentrations for CMA and EE were reached within 1 and 2 hr after taking the study drug. Peak plasma concentrations of CMA were approximately 1600 pg/mL after single-dose administration and 2000 pg/mL after multiple dosing. CMA and EE showed linear pharmacokinetics throughout six cycles, with constant trough values of approximately 400-500 pg/mL for CMA and 20-40 pg/mL for EE. Mass balance factors were 1.2-1.4 for CMA and 1.6-1.7 for EE, and accumulation factors were 1.7-2 for CMA and 1.7-1.8 for EE. Mean t(1/2,z) of CMA was approximately 25 hr after single dosing and 36-39 hr at steady state. In the excretion balance study, mean dose of CMA recovered was 87.3+/-6.4%, with urinary and fecal excretion accounting for 45% and 42%, respectively. The pharmacokinetics of CMA and EE is linear after multiple dosing and remains stable during long-term administration, once steady state is reached. The t(1/2,z) of CMA was 36-39 hr after multiple dosing, which is considerably shorter than the 80 hr often quoted in the literature.
The bioavailability and bioequivalence of two different film coated tablets containing ethinylestradiol and chlormadinone acetate (Bellissima as test and the respective preparation from the originator as reference) were investigated in 20 healthy female volunteers after oral single-dose administration. The study was performed according to a single-center, randomised, single-dose, 2-way cross-over design with a wash-out phase of 28 days. Blood samples for pharmacokinetic profiling were taken up to 168 hr post-dose, and ethinylestradiol and chlormadinone acetate plasma concentrations were determined with a validated LC-MS/MS method. The observed mean maximum plasma concentrations (Cmax) of ethinylestradiol were 124.96 pg/mL (test) and 129.12 pg/mL (reference). In the case of chlormadinone acetate, Cmax averaged 6.9566 ng/mL (test) and 6.6663 ng/mL (reference). The geometric means of area under the plasma concentration-time curve (AUC(0-infinity)) of ethinylestradiol were 1292.35 pg/mL x hr (test) and 1380.49 pg/mL x hr (reference). For chlormadinone acetate, geometric means of AUC(0-infinity) were 53.322 ng/mL x hr (test) and 58.111 ng/mL x hr (reference). The median of tmax of ethinylestradiol was 1.5 hr for both test and reference and the median of tmax of chlormadinone acetate 1.0 hr (test) and 1.5 hr (reference). Plasma elimination half-lives (t1/2) of ethinylestradiol were 14.96 hr (test) and 15.41 hr (reference) and of chlormadinone acetate 56.63 hr (test) and 56.17 hr (reference), respectively. Both primary target parameters AUC(0-infinity) and Cmax were tested parametrically by analysis of variance (ANOVA). The point estimator and the 90% confidence intervals for the AUC(0-infinity) ratio (test/reference: 93.72% [86.62%-101.39%]) indicate high similarity of both formulations with respect to the extent of ethinylestradiol exposure. A high degree of similarity was also observed for Cmax of ethinylestradiol, as the point estimator and the 90% confidence interval for the Cmax ratio are 96.18% (90.82%-101.86%). Regarding the AUC(0-infinity) ratio of chlormadinone acetate, the point estimator is 91.60% and the 90% confidence interval 84.08%-99.79%. Furthermore, exchangeability of both formulations is also suggested by the point estimator and 90% confidence of Cmax of this active agent (104.72% [95.76%-114.53%]). Bioequivalence between test and reference formulation was demonstrated since for both ethinylestradiol and chlormadinone acetate all 90% confidence intervals of AUC(0-infinity) and Cmax fall into the generally accepted range of 80%-125%.
After intravenous injection of radiolabelled chlormadinone acetate, the steroid and its metabolites have an initial rapid half-life of 2.4 hours, followed by a slow half-life of 80.1 hours. The mean metabolic clearance rate is 126 L/day for chlormadinone acetate and 42.6 L/day for chlormadinone acetate and its metabolites. The long half-life and slow elimination rate are probably due to accumulation of the drug in fat tissue.

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Metabolism / Metabolites
The major metabolites of chlormadinone acetate are 2alpha- hydroxychlormadinone acetate and 3beta-hydroxychlormadinone acetate. Incubation of chlormadinone acetate with human or rat liver microsomes produces mainly the 3beta-hydroxy metabolite. In contrast, incubation with microsomes from phenobarbital-treated rats produces the 2alpha-hydroxy metabolite, indicating that the metabolite pattern is dependent on the hepatic monoxygenase state.

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Biological Half-Life
... After a single dose of CMA the half-life time is around 34 hours and after multiple dose administration approximately 38 hours. ...
Published data on pharmacokinetic parameters for chlormadinone acetate (CMA) are in part contradictory, especially with regard to terminal half-life (t(1/2,z)). Single and multiple doses of CMA (2 mg) and ethinylestradiol (EE; 0.03 mg) were administered to healthy female volunteers for six menstrual cycles. ... Mean t(1/2,z) of CMA was approximately 25 hr after single dosing and 36-39 hr at steady state. ... The t(1/2,z) of CMA was 36-39 hr after multiple dosing, which is considerably shorter than the 80 hr often quoted in the literature.
The half-life and metabolic clearance rate of chlormadinone acetate were computed after a single iv injection of 60 to 90 mcCi 1-alpha-tritiated-chlormadinone acetate (specific activity 222 mcCi/mg) into 7 women aged 34-52 years. Plasma was extracted with acetone:MeOH for total radioactivity; then extracted with water and ether for free steroid radioactivity; then with n-butanol for conjugated steroid radioactivity; and finally extracted with chloroform:MeOH and chromatographed on thin layer with ether:benzene for specific radioactivity due to chlormadinone acetate. Blood samples were taken at .25, .5, 1, 8, 24 hours and every 24 hours for 5 days. The mean half-life of radioactivity specifically indentified as chlormadinone acetate for the first 24 hours was 2.6 hours, and after 24 hours was 81.8 hours, calculated by TAIT and BURSTEIN's method. ...
After intravenous injection of radiolabelled chlormadinone acetate, the steroid and its metabolites have an initial rapid half-life of 2.4 hours, followed by a slow half-life of 80.1 hours.

Non-Human Toxicity Values
LD50 Rat oral 6400 mg/kg body weight
LD50 Mouse oral 6400 mg/kg body weight
LD50 Mouse intraperitoneal 3 g/kg

Therapeutic Uses
Contraceptives, Oral, Synthetic; Progestational Hormones, Synthetic
Chlormadinone acetate has not been used in the United States since 1970, when the only product (an oral contraceptive) was removed from the market. Its use in the United Kingdom was suspended in the same year. Before suspension, chlormadinone acetate was used in oral contraceptives either together with mestranol as a "sequential" contraceptive or as a "progestogen only" oral contraceptive. Chlormadinone acetate has been used (frequently in combination with mestranol) for treatment of threatened abortion and dysmenorrhea.
Ethinylestradiol/chlormadinone acetate 0.03/2mg (EE/CMA) is a combined monophasic contraceptive pill with anti-androgenic properties. In a large, non-comparative, multicentre trial (< or =24 cycles of treatment per woman) and two (6- and 12-cycle) post-marketing surveillance studies, EE/CMA was effective in preventing pregnancy. EE/CMA was significantly more effective than EE/levonorgestrel 0.03/0.15 mg/day in treating women with mild-to-moderate papulopustular acne of the face and related disorders in a randomized, single-blind, multicentre trial. EE/CMA was well tolerated in clinical trials and the post-marketing surveillance studies. Adverse events were those commonly reported with oral contraceptives. As expected, the most common menstrual disturbances were breakthrough bleeding, spotting and amenorrhea.
Orally active progestogen with antiandrogenic activity; has been used in combinations as an oral contraceptive.
For more Therapeutic Uses (Complete) data for CHLORMADINONE ACETATE (7 total), 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.)