Pharmacodynamics Norethisterone (δ4-noretynodrel), an active metabolite of<unk> .<unk>  has weak progestogenic activity, weak estrogenic activity, and no or only very weak androgenic activity. It is considered to be a prodrug, and for this reason, the metabolites of<unk>  play an important role in its biological activity. As such, the pharmacodynamics of<unk>  cannot be understood without reference to its metabolism.<unk>  is closely related to norethisterone and tibolone, which are the δ4-isomer and the 7α-methyl derivative of<unk> , respectively. It is metabolized in a very similar manner to tibolone, whereas the metabolism of norethisterone differs. Both<unk>  and tibolone are transformed into 3α- and 3β-hydroxylated metabolites and a δ4-isomer metabolite (in the case of<unk> , this being norethisterone), whereas norethisterone is not 3α- or 3β-hydroxylated (and of course does not form a δ4-isomer metabolite). The major metabolites of<unk>  are 3α-hydroxynoretynodrel and to a lesser extent 3β-hydroxynoretynodrel, formed respectively by 3α- and 3β-hydroxysteroid dehydrogenases (AKR1C1–4), while the δ4-isomer norethisterone is a minor metabolite formed in small amounts. Tibolone is considered to be a prodrug of both its 3α- and 3β-hydroxylated and δ4-isomerized metabolites.<unk>  is also thought to be a prodrug, as it is rapidly metabolized and cleared from circulation and shows very weak relative affinity for the progesterone receptor (PR), although it appears to form norethisterone in only minor quantities. Progestogenic activity<unk>  is a relatively weak progestogen, with only about one-tenth of the progestogenic activity of norethisterone. The ovulation-inhibiting dosage of<unk>  is 4.0 mg/day, relative to 0.4 mg/day in the case of norethisterone. Conversely, the endometrial transformation dosage of<unk>  is 150 mg per cycle, relative to 120 mg per cycle for norethisterone. In terms of the PR,<unk>  possesses only about 6 to 19% of the affinity of norethisterone for the PRA, whereas the affinity of the two drugs for the PRB is similar<unk>  possesses 94% of the affinity of norethisterone for the PRB). Tibolone and the δ4-isomer metabolite of tibolone have similar affinity for the PRs as<unk>  and norethisterone, respectively, whereas the 3α- and 3β-hydroxylated metabolites of tibolone are virtually devoid of affinity for the PRs. Since the structurally related androgen/anabolic steroid trestolone (7α-methyl-19-nortestosterone) is known to be a potent progestogen, suggesting that a 7α-methyl substitution does not interfere with progestogenic activity, 3α- and 3β-hydroxynoretynodrel likely are devoid of affinity for the PR similarly to the 3α- and 3β-hydroxylated metabolites of tibolone. Androgenic activity<unk>  has been said to possess no or only very weak androgenic activity. This is in contrast to norethisterone, which shows mild but significant androgenicity. Relative to norethisterone,<unk>  has 45 to 81% lower affinity for the androgen receptor (AR). In accordance, no androgenic effects (such as hirsutism, clitoral enlargement, or voice changes) have been observed with<unk>  even when used in large dosages (e.g., 60 mg/day) for prolonged periods of time (9–12 months) in the treatment of women with endometriosis. Additionally,<unk>  has not been found to virilize female fetuses, in contrast to many other testosterone-derived progestins including ethisterone, norethisterone, and norethisterone acetate. However, at least one case of pseudohermaphroditism (virilized genitalia) has been observed that may have been due to<unk> . The δ4-isomer metabolite of tibolone shows dramatically and disproportionately increased affinity for the AR relative to norethisterone and<unk>  (5.7- to 18.5-fold greater than that of norethisterone), indicating that the 7α-methyl group of tibolone markedly increases its androgenic activity and is responsible for the greater androgenic effects of tibolone relative to<unk> . Estrogenic activity<unk> , unlike most progestins but similarly to etynodiol diacetate, has some estrogenic activity. Relative to other 19-nortestosterone progestins,<unk>  is said to possess much stronger estrogenic activity. In the Allen–Doisy test of estrogenicity in animals,<unk>  has been reported to possess 100-fold greater estrogenic activity than norethisterone. Whereas norethisterone has virtually no affinity for the estrogen receptors (ERs),<unk>  shows some, albeit very weak affinity for both the ERα and the ERβ (in terms of relative binding affinity, 0.7% and 0.22% of that of estradiol, respectively). The estrogenic activity of 3α- and 3β-hydroxynoretynodrel has never been assessed. However, while tibolone shows similar affinity for the ERs as<unk> , the 3α- and 3β-hydroxylated metabolites of tibolone have several-fold increased affinity for the ERs. As such, the 3α- and 3β-hydroxylated metabolites of<unk>  may also show increased estrogenic activity, and this may account for the known estrogenic effects of<unk> . The δ4-isomer of tibolone, similarly to norethisterone, is virtually devoid of affinity for the ERs. Neither tibolone nor its metabolites are aromatized, whereas trestolone is readily aromatized similarly to testosterone and 19-nortestosterone, and for these reasons, it is unlikely that<unk>  or its metabolites, aside from norethisterone, are aromatized either. As such, aromatization likely does not play a role in the estrogenic activity of tibolone or<unk> . However, controversy on this matter exists, and other researchers have suggested that tibolone and<unk>  may be aromatized in small amounts to highly potent estrogens (ethinylestradiol and its 7α-methyl derivative, respectively). Pharmacokinetics<unk>  is rapidly absorbed upon oral administration and is rapidly metabolized, disappearing from the circulation within 30 minutes. In terms of plasma protein binding,<unk>  is bound to albumin, and show no affinity itself for sex hormone-binding globulin or corticosteroid-binding globulin. The plasma protein binding of its metabolites, such as norethisterone, may differ however. The major metabolites of<unk>  in the circulation are 3α-hydroxynoretynodrel (formed by ) and to a lesser extent 3β-hydroxynoretynodrel (formed by ), and more minor metabolites of<unk>  are norethisterone (formed by δ5-4-isomerase) and possibly ethinylestradiol (formed by aromatase or possibly other cytochrome P450 enzymes, most likely monooxygenases). Due to its very short elimination half-life and its low affinities for steroid hormone receptors in receptor binding assays,<unk>  is considered to be a prodrug which is rapidly transformed into its active metabolites in the intestines and liver following oral administration. Some researchers have stated that it is specifically a prodrug of norethisterone. According to other researchers however, there is, due to a lack of research, insufficient data to unequivocally show this to be the case at present. About 1% of an oral dose of<unk>  is detected in breast milk. The pharmacokinetics of<unk>  have been reviewed.
Noretynodrel
Buffalopox
Protokylol
Tezacaftor
Oprelvekin
Prasugrel
Co-codaprin
Cangrelor