Pharmacodynamics<unk>  binds with high affinity to the progesterone receptor (PR) and mineralocorticoid receptor (MR), with lower affinity to the androgen receptor (AR), and with very low affinity to the glucocorticoid receptor (GR). It is an agonist of the PR and an antagonist of the MR and AR, and hence is a progestogen, antimineralocorticoid, and antiandrogen.<unk>  has no estrogenic activity and no appreciable glucocorticoid or antiglucocorticoid activity. Relative affinities (%) of<unk>  and related steroids Progestogen<unk>  19–70 1–65 0–1 1–6 100–500 0 0 Progesterone 100 0–80 0–1 6–35 100–1000 0 0 Notes: Values are percentages (%). Reference ligands (100%) were progesterone for the , metribolone for the , estradiol for the , dexamethasone for the , and aldosterone for the . Sources: Progestogenic activity<unk>  is an agonist of the PR, the biological target of progestogens like progesterone. It has about 35% of the affinity of promegestone for the PR and about 19 to 70% of the affinity of progesterone for the PR.<unk>  has antigonadotropic and functional antiestrogenic effects as a result of PR activation. The ovulation-inhibiting dosage of<unk>  is 2 to 3 mg/day. Inhibition of ovulation occurred in about 90% of women at a dose of 0.5 to 2 mg/day and in 100% of women at a dose of 3 mg/day. The total endometrial transformation dose of<unk>  is about 50 mg per cycle, whereas its daily dose is 2 mg for partial transformation and 4 to 6 mg for full transformation. The medication acts as a contraceptive by activating the PR, which suppresses the secretion of luteinizing hormone, inhibits ovulation, and alters the cervical membrane and endometrium. Due to its antigonadotropic effects,<unk>  inhibits the secretion of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and suppresses gonadal sex hormone production, including of estradiol, progesterone, and testosterone.<unk>  alone at 4 mg/day has been found to suppress estradiol levels in premenopausal women to about 40 to 80 pg/mL depending on the time of the cycle. No studies of the antigonadotropic effects of<unk>  or its influence on hormone levels appear to have been conducted in men. In male cynomolgus monkeys however, 4 mg/kg/day oral<unk>  strongly suppressed testosterone levels. Antimineralocorticoid activity<unk>  is an antagonist of the MR, the biological target of mineralocorticoids like aldosterone, and hence is an antimineralocorticoid. It has about 100 to 500% of the affinity of aldosterone for the MR and about 50 to 230% of the affinity of progesterone for the MR.<unk>  is about 5.5 to 11 times more potent as an antimineralocorticoid than spironolactone in animals. Accordingly, 3 to 4 mg<unk>  is said to be equivalent to about 20 to 25 mg spironolactone in terms of antimineralocorticoid activity. It has been said that the pharmacological profile of<unk>  more closely resembles that of progesterone than other progestins due to its antimineralocorticoid activity.<unk>  is the only clinically used progestogen with prominent antimineralocorticoid activity besides progesterone. For comparison to progesterone, a 200 mg dose of oral progesterone is considered to be approximately equivalent in antimineralocorticoid effect to a 25 to 50 mg dose of spironolactone. Both<unk>  and progesterone are actually weak partial agonists of the MR in the absence of mineralocorticoids. Due to its antimineralocorticoid activity,<unk>  increases natriuresis, decreases water retention and blood pressure, and produces compensatory increases in plasma renin activity as well as circulating levels and urinary excretion of aldosterone. This has been shown to occur at doses of 2 to 4 mg/day. Similar effects occur during the luteal phase of the menstrual cycle due to increased progesterone levels and the resulting antagonism of the MR. Estrogens, particularly ethinylestradiol, activate liver production of angiotensinogen and increase levels of angiotensinogen and angiotensin II, thereby activating the renin–angiotensin–aldosterone system. As a result, they can produce undesirable side effects including increased sodium excretion, water retention, weight gain, and increased blood pressure. Progesterone and<unk>  counteract these undesirable effects via their antimineralocorticoid activity. Accumulating research indicates that antimineralocorticoids like<unk>  and spironolactone may also have positive effects on adipose tissue and metabolic health. Antiandrogenic activity<unk>  is an antagonist of the AR, the biological target of androgens like testosterone and dihydrotestosterone (DHT). It has about 1 to 65% of the affinity of the synthetic anabolic steroid metribolone for the AR. The medication is more potent as an antiandrogen than spironolactone, but is less potent than cyproterone acetate, with about 30% of its antiandrogenic activity in animals. Progesterone displays antiandrogenic activity in some assays similarly to<unk> , although this issue is controversial and many researchers regard progesterone as having no significant antiandrogenic activity.<unk>  shows antiandrogenic effects on the serum lipid profile, including higher HDL cholesterol and triglyceride levels and lower LDL cholesterol levels, at a dose of 3 mg/day in women. The medication does not inhibit the effects of ethinylestradiol on sex hormone-binding globulin (SHBG) and serum lipids, in contrast to androgenic progestins like levonorgestrel but similarly to other antiandrogenic progestins like cyproterone acetate. SHBG levels are significantly higher with ethinylestradiol and cyproterone acetate than with ethinylestradiol and<unk> , owing to the more potent antiandrogenic activity of cyproterone acetate relative to<unk> . Androgenic progestins like levonorgestrel have been found to inhibit the procoagulatory effects of estrogens like ethinylestradiol on hepatic synthesis of coagulation factors, whereas this may occur less or not at all with weakly androgenic progestins like desogestrel and antiandrogenic progestins like<unk> . Other activity<unk>  stimulates the proliferation of MCF-7 breast cancer cells in vitro, an action that is independent of the classical PRs and is instead mediated via the progesterone receptor membrane component-1 (PGRMC1). Certain other progestins act similarly in this assay, whereas progesterone acts neutrally. It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in clinical studies. Pharmacokinetics Absorption The oral bioavailability of<unk>  is between 66 and 85%. Peak levels occur 1 to 6 hours after an oral dose. Levels are about 27 ng/mL after a single 4 mg dose. There is 1.5- to 2-fold accumulation in<unk>  levels with continuous administration, with steady-state levels of<unk>  achieved after 7 to 10 days of administration. Peak levels of<unk>  at steady state with 4 mg/day<unk>  are about 41 ng/mL. With the combination of 30 μg/day ethinylestradiol and 3 mg/day<unk> , peak levels of<unk>  after a single dose are 35 ng/mL, and levels at steady state are 60 to 87 ng/mL at peak and 20 to 25 ng/mL at trough. The pharmacokinetics of oral<unk>  are linear with a single dose across a dose range of 1 to 10 mg. Intake of<unk>  with food does not influence the absorption of<unk> . Distribution The distribution half-life of<unk>  is about 1.6 to 2 hours. The apparent volume of distribution of<unk>  is approximately 4 L/kg. The plasma protein binding of<unk>  is 95 to 97%. It is bound to albumin and 3 to 5% circulates freely or unbound.<unk>  has no affinity for sex hormone-binding globulin (SHBG) or corticosteroid-binding globulin (CBG), and hence is not bound by these plasma proteins in the circulation. Metabolism The metabolism of<unk>  is extensive. It is metabolized into the acid form of<unk>  by opening of its lactone ring. The medication is also metabolized by reduction of its double bond between the C4 and C5 positions and subsequent sulfation. The two major metabolites of<unk>  are<unk>  acid and 4,5-dihydrodrospirenone 3-sulfate, and are both formed independently of the cytochrome P450 system. Neither of these metabolites are known to be pharmacologically active.<unk>  also undergoes oxidative metabolism by CYP3A4. Elimination<unk>  is excreted in urine and feces, with slightly more excreted in feces than in urine. Only trace amounts of unchanged<unk>  can be found in urine and feces. At least 20 different metabolites can be identified in urine and feces.<unk>  and its metabolites are excreted in urine about 38% as glucuronide conjugates, 47% as sulfate conjugates, and less than 10% in unconjugated form. In feces, excretion is about 17% glucuronide conjugates, 20% sulfate conjugates, and 33% unconjugated. The elimination half-life of<unk>  is between 25 and 33 hours. The half-life of<unk>  is unchanged with repeated administration. Elimination of<unk>  is virtually complete 10 days after the last dose.
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