Pharmacodynamics Norelgestromin, also known as 17β-deacetylnorgestimate, the main active metabolite of<unk> .<unk>  is a rapidly and completely converted prodrug, mainly of norelgestromin (17β-deacetylnorgestimate or levonorgestrel 3-oxime), but also of levonorgestrel (3-keto-17β-deacetylnorgestimate) to a lesser extent (22 ± 6% of an administered dose or about 40–70 µg) and of levonorgestrel acetate (levonorgestrel 17β-acetate) in very small amounts. Via its active metabolites,<unk>  has progestogenic activity, antigonadotropic effects, very weak androgenic activity, and no other important hormonal activity. Relative affinities (%) of<unk>  and metabolites Compound<unk>  15 0 0 1 0 0 0 Norelgestromin () 10 0 ? ? ? 0 ? Levonorgestrel () 150–162 45 0 1–8 17–75 50 0 Levonorgestrel 17β-acetate () 135 ? 0 ? ? 0 ? Notes: Values are percentages (%). Reference ligands (100%) were promegestone for the , metribolone for the , for the , for the , aldosterone for the , for , and cortisol for . Sources: Progestogenic activity<unk>  is a progestogen, or an agonist of the progesterone receptor. The relative binding affinities of<unk>  and its active metabolites for the progesterone receptor compared to promegestone (100%) are 15% for<unk> , 10% for norelgestromin, 150% for levonorgestrel, and 135% for levonorgestrel acetate. Because of their low concentrations,<unk>  and levonorgestrel acetate are not thought to contribute significantly to the biological activity of<unk> . In addition, although levonorgestrel binds to the progesterone receptor with much higher affinity than norelgestromin, levonorgestrel has high affinity for sex hormone-binding globulin (SHBG) (87% of that of testosterone), which may limit its activity, whereas norelgestromin does not bind to SHBG. The ovulation-inhibiting dosage of<unk>  is 200 µg/day. Androgenic activity In addition to its progestogenic activity,<unk>  has weak androgenic activity. However, the medication shows less androgenic activity than related 19-nortestosterone progestins like levonorgestrel and norethisterone.<unk>  and norelgestromin have negligible affinity for the androgen receptor (both 0% of the affinity of metribolone), while levonorgestrel has considerable affinity for the androgen receptor (45% of that of metribolone). In addition to their lack of affinity for the androgen receptor,<unk>  and norelgestromin have virtually no affinity for SHBG, and therefore do not displace testosterone from this carrier protein (although levonorgestrel does still bind with high affinity to SHBG and hence could increase free testosterone levels via occupation of SHBG). In accordance, clinical trials of<unk>  have observed minimal androgenic side effects in women treated with the medication. As an example, clinical studies have found that<unk>  does not appreciably inhibit the increase in SHBG levels produced by ethinylestradiol. This is of interest because estrogens increase and androgens decrease liver production of SHBG and by extension circulating levels of SHBG. The relative binding affinity of<unk>  and its metabolite norelgestromin for the rat prostatic androgen receptor (AR) are 0.3% and 1.3% of those of dihydrotestosterone (DHT), respectively, whereas the respective values for levonorgestrel and gestodene are 22% and 15%. Based on these findings, the ratios of AR to PR binding are 219 for<unk>  and 48 for norelgestromin, whereas the ratios for progesterone, levonorgestrel, and gestodene are 93, 11, and 28, respectively. As such,<unk>  and norelgestromin would appear to have much lower androgenic potency than other 19-nortestosterone progestins. However, levonorgestrel is an important metabolite of both<unk>  and norelgestromin, and it may serve to increase their androgenic potency to some degree. When<unk>  is combined with ethinylestradiol, which is potently antiandrogenic, there are only antiandrogenic effects overall and the combination is suitable for treatment of hyperandrogenism. Other activities<unk>  and its active metabolites do not bind to other steroid hormone receptors besides the progesterone and androgen receptors and hence have no other off-target hormonal activity. This includes estrogenic, glucocorticoid, antimineralocorticoid, and neurosteroid activity. However, levonorgestrel has been found to inhibit 5α-reductase and hepatic cytochrome P450 enzymes in vitro to some extent. Pharmacokinetics<unk>  is rapidly and almost completely metabolized into its active metabolites, mainly norelgestromin (the primary active metabolite) and to a lesser extent levonorgestrel, upon oral ingestion. As a result, only very low concentrations (70 pg/mL) of<unk>  itself are detectable in the circulation, and only for about 6 hours after an oral dose. The oral bioavailability of<unk>  is unknown. This is due to the rapid and extensive metabolism of<unk> , which makes determination of overall bioavailability difficult and necessitates methods other than area-under-the-curve (AUC) to do so. Peak levels of norelgestromin (3,500 pg/mL) are reached at approximately 2 hours following administration of<unk> . Co-administration of<unk>  with a high-fat meal has been found to significantly decrease peak levels of norelgestromin, although the area-under-the-curve levels of norelgestromin are not significantly altered by food. Steady-state levels of norelgestromin and levonorgestrel are reached within 21 days of treatment with<unk> . There is an approximate 2-fold accumulation in levels of norelgestromin and a non-linear approximate 8-fold accumulation in levels of levonorgestrel with continuous administration of<unk> . The accumulation of levonorgestrel is thought to be a result of its high affinity for SHBG, which limits its biological activity. The plasma protein binding of norelgestromin is approximately 99% and it is bound to albumin but not to SHBG. Conversely, levonorgestrel is approximately 98% bound to plasma proteins and is bound to both albumin and SHBG.<unk>  is extensively metabolized into its active metabolites during first-pass metabolism in the liver and intestines. The major metabolite of<unk>  is norelgestromin and is formed from<unk>  via deacetylation in the liver and intestines. A more minor metabolite of<unk>  is levonorgestrel, which accounts for 20 to 25% (22 ± 6%) of an administered dose or about 40 to 70 µg<unk> , and a very minor metabolite of<unk>  is levonorgestrel 17β-acetate. Both of these metabolites are active similarly to norgelstromin. With a typical oral contraceptive dosage of<unk>  of 200 to 250 µg/day, an amount of 50 to 60 µg/day levonorgestrel may be produced. This is similar to the ovulation-inhibiting dosage of levonorgestrel, and suggests that<unk>  may act in considerable part as a prodrug specifically of levonorgestrel. Following their formation, the active metabolites of<unk>  are inactivated via reduction, hydroxylation, and conjugation into levonorgestrel metabolites. The terminal half-life of norelgestromin is between 17 and 37 hours and of levonorgestrel is between 24 and 32 hours. The metabolites of<unk>  are eliminated 47% in urine and 37% in feces. Unchanged<unk>  is undetectable in urine.
Norgestimate
Nandrolone cyclohexylpropionate
Levonorgestrel
Ergometrine
Drostanolone propionate
Nandrolone furylpropionate
Etonogestrel
Norbormide