Pharmacodynamics<unk>  possesses a complex pharmacology, with multiple mechanisms of action. These include direct binding to and activation of sex hormone receptors, direct inhibition of enzymes involved in steroidogenesis, and direct binding to and occupation of steroid hormone carrier proteins and consequent displacement of steroid hormones from these proteins. The drug is characterized as a weak androgen and anabolic, a weak progestogen, a weak antigonadotropin, a weak steroidogenesis inhibitor, and a functional antiestrogen. Modulation of steroid hormone receptors<unk>  is described as a possessing high affinity for the androgen receptor (AR), moderate affinity for the progesterone receptor (PR) and glucocorticoid receptor (GR), and poor affinity for the estrogen receptor (ER). As an androgen,<unk>  is described as weak, being about 200-fold less potent than testosterone in bioassays. The drug can act as both an agonist and antagonist of the PR depending on the bioassay, indicating that it could be regarded as a selective progesterone receptor modulator (SPRM). Although the affinity and efficacy of<unk>  itself at the PR are relatively low, ethisterone, one of the major metabolites of<unk> , is described as a weak progestogen (and has been employed clinically as a progestogen), and this presumably serves to increase the in vivo progestogenic activity of<unk> . The activity of<unk>  at the ER is considered to be minimal, although at very high concentrations the drug can act significantly as an ER agonist.<unk>  is considered to act significantly as an agonist of the GR, and, thus, as a glucocorticoid. In accordance, it can suppress the immune system at sufficient dosages. Relative affinities (%) of<unk>  and metabolites Steroid<unk>  9 8 ? a ? 40 10 Ethisterone 35 b c 4 120b ? 100 ? Notes: Values are percentages (%). Reference ligands (100%) were progesterone for the , testosterone (c = ) for the , cortisol for the (b = dexamethasone), aldosterone for the , for , and cortisol for . a = 1-hour incubation time (4 hours is standard for this assay; may affect affinity value). Sources: Absolute affinities (nM) of<unk>  Receptor Affinity Action Androgen receptor 90 Agonist Progesterone receptor 6,000 Agonist–antagonist Glucocorticoid receptor 5,000 Agonist Estrogen receptor 80,000 Agonist Sources: Inhibition of steroidogenesis enzymes<unk>  has been found to act as an inhibitor, to varying extents, of a variety of steroidogenic enzymes, including cholesterol side-chain cleavage enzyme, 3β-hydroxysteroid dehydrogenase/Δ5-4 isomerase, 17α-hydroxylase, 17,20-lyase, 17β-hydroxysteroid dehydrogenase, 21-hydroxylase, and 11β-hydroxylase. It has also been found to be a weak inhibitor of steroid sulfatase (Ki = 2.3–8.2 μM), the enzyme that converts into and estrone sulfate into estrone (which can then respectively be transformed into estrone (with androstenedione as an intermediate) and estradiol), though another study reported its inhibition to be potent and potentially clinically relevant. Although in contradiction with the above data, another study found that<unk>  weakly inhibited aromatase as well, with 44% inhibition at a concentration of 10 μM. In accordance with its steroidogenesis inhibition, clinical studies have demonstrated that<unk>  directly and markedly inhibits adrenal, ovarian, and testicular steroidogenesis in vivo. The enzymatic production of estradiol, progesterone, and testosterone have all specifically been found to be inhibited.<unk>  at steroiodgenic enzymes Enzyme Affinity (Ki) Inhibition type Estimated inhibition at 2 μM Cholesterol side-chain cleavage enzyme 20 μM Competitive ? 3β-Hydroxysteroid dehydrogenase/Δ5-4 isomerase 5.8 μM Competitive 4.3% 17α-Hydroxylase 2.4 μM Competitive 2.9% 17,20-Lyase 1.9 μM Competitive 3.9% 17β-Hydroxysteroid dehydrogenase 4.4 μM Competitive 15% 21-Hydroxylase 0.8 μM Competitive 37% 11β-Hydroxylase 1 μM Competitive 21% Aromatase >100 μM – 0% Sources: For reference, circulating concentrations of<unk>  are in the range of 2 μM at a dosage of 600 mg/day in women. Occupation and downregulation of carrier proteins Protein binding of testosterone in women Group Free Albumin SHBG Normal (no<unk>  1% 39% 60%<unk>  treatment 3% 79% 18% Sources:<unk>  is known to bind to two steroid hormone carrier proteins: sex hormone-binding globulin (SHBG), which binds androgens and estrogens; and corticosteroid-binding globulin (CBG), which binds progesterone and cortisol. Binding of<unk>  to SHBG is considered to be more important clinically. By occupying SHBG and CBG,<unk>  increases the ratio of free to plasma protein-bound testosterone, estradiol, progesterone, and cortisol. The table to the right shows the difference in testosterone levels in premenopausal women treated with<unk> . As can be seen, the percentage of free testosterone is tripled in women being treated with<unk> . The ability of<unk>  to increase free testosterone levels suggests that a portion of its weak androgenic effects are mediated indirectly by facilitating the activity of testosterone and dihydrotestosterone through the displacement of them from SHBG. In addition to binding to and occupying SHBG however,<unk>  also decreases the hepatic production of SHBG and therefore SHBG levels, and so downregulation of SHBG may be involved as well.<unk>  likely decreases hepatic production of SHBG by reducing estrogenic and increasing androgenic activity in the liver (as androgens and estrogens decrease and increase, respectively, hepatic SHBG synthesis). In accordance with the notion that suppression of SHBG is involved in the androgenic effects of<unk> , the drug has synergistic rather than additive androgenic effects in combination with testosterone in bioassays (which is most likely secondary to the increased free testosterone levels). It is noteworthy that 2-hydroxymethylethisterone, a major metabolite of<unk> , circulates at concentrations 5–10 times greater than those of<unk>  and is twice as potent as<unk>  in displacing testosterone from SHBG. As such, most of the occupation of SHBG by<unk>  may actually be due to this metabolite. Antigonadotropic activity Via its weak progestogenic and androgenic activity, through activation of the PR and AR in the pituitary gland,<unk>  produces antigonadotropic effects. Although its does not significantly affect basal luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in premenopausal women (and hence does not profoundly suppress gonadotropin or sex hormone levels like other, stronger antigonadotropins do), the drug prevents the mid-cycle surge in the levels of these hormones during the menstrual cycle. By doing this, it suppresses increases in estrogen and progesterone levels at this time and prevents ovulation. Mechanism of action in endometriosis Because<unk>  reduces estrogen production and levels, it has functional antiestrogenic properties. The combination of its antiestrogenic, androgenic, and progestogenic or antiprogestogenic actions cause atrophy of the endometrium, which alleviates the symptoms of endometriosis. Effects in men In men,<unk>  has been found to inhibit gonadotropin secretion and markedly decrease testosterone levels, likely due to its actions as a steroidogenesis inhibitor and antigonadotropin. However, even at the highest dosage assessed (800 mg/day), spermatogenesis remained unaffected. Pharmacokinetics The bioavailability of<unk>  is low. In addition, circulating levels of<unk>  do not increase proportionally with increasing doses, indicating that there is a saturation of bioavailability. With single-dose administration, it has been found that a 4-fold increase in dosage of<unk>  increased peak levels only by 1.3- and 2.2-fold and area-under-the-curve levels by 1.6- and 2.5-fold in the fasted and fed states, respectively. Similar findings were observed for chronic administration. Intake of<unk>  with food (>30 grams of fat) has been found to increase the bioavailability and peak levels of<unk>  by 3- to 4-fold with a single dose and by 2- to 2.5-fold with chronic administration. Following administration of<unk> , peak concentrations occur after 2 to 8 hours, with a median of 4 hours. Steady-state levels of<unk>  are achieved after 6 days of twice-daily administration.<unk>  is lipophilic and can partition into cell membranes, which indicates that it is likely to distribute deeply into tissue compartments. The volume of distribution of<unk>  is 3.4 L.<unk>  is known to be plasma protein bound to albumin, SHBG, and CBG.<unk>  is metabolized in the liver by enzymes such as CYP3A4. Its elimination half-life has varied across studies, but has been found to be 3 to 10 hours after a single dose and 24 to 26 hours with repeated administration. The major metabolites of<unk>  are 2-hydroxymethylethisterone (also known as 2-hydroxymethyldanazol; formed by CYP3A4 and described as inactive) and ethisterone (a progestogen and androgen), and other, minor metabolites include δ2-hydroxymethylethisterone, 6β-hydroxy-2-hydroxymethylethisterone, and δ1-6β-hydroxy-2-hydroxymethylethisterone. At least 10 different metabolites have been identified.<unk>  is eliminated in urine and feces, with the two primary metabolites in urine being 2-hydroxymethylethisterone and ethisterone.
Danazol
Gestodene
Algestone
Formestane
Telapristone
Hexestrol
Mifepristone
Promegestone