Pharmacodynamics NOMAC has progestogenic activity, antigonadotropic effects, antiandrogenic activity, and no other important hormonal activity. Relative affinities (%) of<unk>  and related steroids Compound<unk>  125 42 0 6 0 0 0 65 5 0 30 0 0 0 50 0 0 10 100 0 36 Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the , metribolone for the , estradiol for the , dexamethasone for the , aldosterone for the , dihydrotestosterone for , and cortisol for . Sources: Progestogenic activity NOMAC is a potent and pure progestogen, acting as a selective, high-affinity full agonist of the progesterone receptor (PR) (Ki = 3 nM, 67–303% of the relative binding affinity of progesterone), and is said to have higher potency and substantially improved selectivity for the PR relative to medroxyprogesterone<unk>  (the 6-hydrogenated or non-6-7-double bonded analogue of megestrol<unk>  and the most widely used progestin). In accordance, NOMAC is a potent antigonadotropin and exhibits no androgenic, estrogenic, glucocorticoid, or antimineralocorticoid activity, but does possess some antiandrogenic activity. Due to its potent antigonadotropic activity, NOMAC has strong functional antiandrogenic and antiestrogenic effects when administered at sufficiently high doses. Like many other progestogens, NOMAC has been assessed and found in vitro to inhibit the conversion of estrone sulfate to estrone (via inhibition of steroid sulfatase) and estrone to estradiol (via inhibition of ) at high concentrations (0.5–50 μM) and to stimulate the conversion of estrone into estrone sulfate (via activation of estrogen sulfotransferase activity) at low concentrations (0.05–0.5 μM), whilst not affecting aromatase activity at any tested concentration (up to 10 μM). These activities appear to be PR-dependent, as NOMAC is more potent in producing them in PR-rich cell lines (e.g., T47-D vs. MCF-7) and they can be blocked by the PR antagonist mifepristone (RU-486). Although the clinical implications of these actions are unclear and they have yet to be confirmed in vivo or assessed in clinical studies, it has been suggested that NOMAC and certain other progestins may be useful in the treatment of -positive breast cancer by decreasing levels of estrogens in breast tissue. In accordance with this notion, in vitro, NOMAC does not have proliferative effects on breast tissue, does not stimulate breast cell proliferation via (similarly to progesterone), and reduces the breast proliferative effects of estradiol when added to it in medium. Antigonadotropic effects The ovulation-inhibiting dosage of NOMAC is 1.5 to 5 mg/day. Due to its high antigonadotropic activity and its long elimination half-life, the contraceptive effectiveness of NOMAC is maintained even when a dose is missed; clinical studies found no increased incidence of pregnancy with one missed pill of Zoely or even with two missed pills during days 8 to 17 of the menstrual cycle. Antiandrogenic activity NOMAC acts as an antagonist of the androgen receptor (AR), with approximately 12 to 31% of the relative binding affinity of testosterone for the AR and 42% of the affinity of metribolone for the AR. Estimates of the antiandrogenic potency of NOMAC are mixed, ranging from 5 to 20%, 20 to 30%, and 90% of that of cyproterone<unk>  depending on the source. The antiandrogenic activity of NOMAC may be useful in helping to alleviate acne, seborrhea, and other androgen-dependent symptoms in women. Other activity Certain progestins have been found to stimulate 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). Progesterone and NOMAC, in contrast, act neutrally in this assay. It is unclear if these findings may explain the different risks of breast cancer observed with progesterone and progestins in clinical studies. Pharmacokinetics NOMAC is well-absorbed, with an oral bioavailability of 63%. It is 97.5 to 98% protein-bound, to albumin, and does not bind to sex hormone-binding globulin or corticosteroid-binding globulin. The medication is metabolized hepatically via hydroxylation by the enzymes CYP3A3, CYP3A4, and CYP2A6. It has six main metabolites, all of which have no or minimal progestogenic activity. The elimination half-life of NOMAC is approximately 50 hours, with a range of 30 to 80 hours. Steady-state concentrations of NOMAC are achieved after five days of repeated administration. As Zoely (2.5 mg/day NOMAC), the average circulating concentrations of NOMAC are 4.5 ng/mL at steady-state, with minimum and maximum concentrations of 3.1 ng/mL and 12.3 ng/mL, respectively. The medication is eliminated via urine and feces.
Nomegestrol acetate
Algestone acetonide
Promegestone
Algestone
Gestodene
Ethinylestradiol sulfonate
Hydroxyprogesterone acetate
Algestone acetophenide