Pharmacodynamics<unk>  is a selective estrogen receptor modulator (SERM). That is, it is a selective mixed agonist–antagonist of the estrogen receptors (ERs), with estrogenic actions in some tissues and antiestrogenic actions in other tissues. The medication has estrogenic effects in bone, partial estrogenic effects in the uterus and liver, and antiestrogenic effects in the breasts. The affinity of<unk>  for the ER is similar to that of tamoxifen. In studies using rat ER,<unk>  had about 1.4% and tamoxifen had about 1.6% of the affinity of estradiol for the ER. The affinities (Ki) of<unk>  at the human ERs have been reported as 20.3 ± 0.1 nM for the ERα and 15.4 ± 3.1 nM for the ERβ. In other rat ER studies,<unk>  had 3–9% of the affinity of estradiol for the ER while its metabolites N-desmethyltoremifene and 4-hydroxytoremifene had 3–5% and 64–158% of the affinity of estradiol for the ER, respectively. The affinity of another metabolite, 4-hydroxy-N-desmethyltoremifene, was not assessed. 4-Hydroxytoremifene showed about 100-fold higher antiestrogenic potency than<unk>  in vitro in one study, but not in another. 4-Hydroxy-N-desmethyltoremifene has also been found to be strongly antiestrogenic in vitro. The metabolites of<unk> , particularly 4-hydroxytoremifene, may contribute importantly to the clinical activity of the medication. On the other hand, some authorities consider<unk>  not to be a prodrug.<unk>  is very similar to tamoxifen and shares most of its properties. There are some indications that<unk>  may be safer than tamoxifen as it is not a hepatocarcinogen in animals and may have less potential for genotoxicity. However, clinical studies have found no significant differences between<unk>  and tamoxifen, including in terms of effectiveness, tolerability, and safety, and hence the clinical use of<unk>  has been somewhat limited.<unk>  is thought to have about one-third of the potency of tamoxifen; i.e., 60 mg<unk>  is roughly equivalent to 20 mg tamoxifen in the treatment of breast cancer.<unk>  has been found to have antigonadotropic effects in postmenopausal women, progonadotropic effects in men, to increase sex hormone-binding globulin levels, and to decrease insulin-like growth factor 1 levels by about 20% in postmenopausal women and men. In addition to its activity as a SERM, 4-hydroxytoremifene is an antagonist of the estrogen-related receptor γ (ERRγ). Pharmacokinetics Absorption The bioavailability of<unk>  has not been precisely determined but is known to be good and has been estimated to be approximately 100%. Levels of<unk>  at steady state with a dosage of 60 mg/day are 800 to 879 ng/mL. Levels of N-desmethyltoremifene at steady state with<unk>  were 3,058 ng/mL at 60 mg/day, 5,942 ng/mL at 200 mg/day, and 11,913 ng/mL at 400 mg/day. Levels of 4-hydroxytoremifene at steady state with<unk>  were 438 ng/mL at 200 mg/day and 889 ng/mL at 400 mg/day. Concentrations of<unk>  increase linearly across a dose range of 10 to 680 mg. Distribution<unk>  is 99.7% bound to plasma proteins, with 92% bound specifically to albumin, about 6% to β1 globulin fraction, and about 2% to a fraction between albumin and α1 globulins. The apparent volume of distribution of<unk>  ranged from 457 to 958 L. Metabolism<unk>  is metabolized in the liver primarily by CYP3A4 and then undergoes secondary hydroxylation. The metabolites of<unk>  include N-desmethyltoremifene, 4-hydroxytoremifene, and 4-hydroxy-N-desmethyltoremifene, among others. Ospemifene (deaminohydroxytoremifene) is also a major metabolite of<unk> . Elimination The elimination half-life of<unk>  is 3 to 7 days in healthy individuals. In people with impaired liver function, the half-life is 11 days. The elimination half-lives of the metabolites of<unk>  are 5 to 21 days for N-desmethyltoremifene, 5 days for 4-hydroxytoremifene, and 4 days for ospemifene. The long elimination half-lives of<unk>  and its metabolites are thought to be due to enterohepatic recirculation and high plasma protein binding.<unk>  is eliminated 70% in the feces, as metabolites.
Toremifene
Tiotixene
Daridorexant
Rauwolscine
Tasimelteon
Acolbifene
Mitapivat
Seltorexant