Pharmacodynamics Selective estrogen receptor modulator activity Crystallographic structure of afimoxifene (carbon = white, oxygen = red, nitrogen = blue) complexed with ligand binding domain of estrogen receptor alpha (ERα) (cyan ribbon).<unk>  acts as a selective estrogen receptor modulator (SERM), or as a partial agonist of the estrogen receptors (ERs). It has mixed estrogenic and antiestrogenic activity, with its profile of effects differing by tissue. For instance,<unk>  has predominantly antiestrogenic effects in the breasts but predominantly estrogenic effects in the uterus and liver. In breast tissue,<unk>  acts as an ER antagonist so that transcription of estrogen-responsive genes is inhibited. A beneficial side effect of<unk>  is that it prevents bone loss by acting as an ER agonist (i.e., mimicking the effects of estrogen) in this cell type. Therefore, by inhibiting osteoclasts, it prevents osteoporosis. When<unk>  was launched as a drug, it was thought that<unk>  would act as an ER antagonist in all tissues, including bone, and therefore it was feared that it would contribute to osteoporosis. It was therefore very surprising that the opposite effect was observed clinically. Hence<unk> 's tissue selective action directly led to the formulation of the concept of SERMs.<unk>  is a long-acting SERM, with a nuclear retention of the ER–tamoxifen (or metabolite) complex of greater than 48 hours. It has relatively little affinity for the ERs itself and instead acts as a prodrug of active metabolites such as endoxifen (4-hydroxy-N-desmethyltamoxifen) and afimoxifene (4-hydroxytamoxifen; 4-OHT). These metabolites have approximately 30 to 100 times greater affinity for the ERs than<unk>  itself. Per one study,<unk>  had 7% and 6% of the affinity of estradiol for the ERα and ERβ, respectively, whereas afimoxifene had 178% and 338% of the affinity of estradiol for the ERα and ERβ, respectively. Hence, afimoxifene showed 25-fold higher affinity for the ERα and 56-fold higher affinity for the ERβ than<unk> . The antiestrogenic potencies of endoxifen and afimoxifene are very similar. However, endoxifen occurs in much higher concentrations than afimoxifene and is now thought to be the major active form of<unk>  in the body.<unk>  binds to ER competitively (with respect to the endogenous agonist estrogen) in tumor cells and other tissue targets, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. It is a nonsteroidal agent with potent antiestrogenic properties which compete with estrogen for binding sites in breast and other tissues.<unk>  causes cells to remain in the G0 and G1 phases of the cell cycle. Because it prevents (pre)cancerous cells from dividing but does not cause cell death,<unk>  is cytostatic rather than cytocidal.<unk>  binds to ER, the ER/tamoxifen complex recruits other proteins known as co-repressors, and the complex then binds to DNA to modulate gene expression. Some of these proteins include NCoR and SMRT.<unk>  function can be regulated by a number of different variables including growth factors.<unk>  needs to block growth factor proteins such as ErbB2/HER2 because high levels of ErbB2 have been shown to occur in<unk>  resistant cancers.<unk>  seems to require a protein PAX2 for its full anticancer effect. In the presence of high PAX2 expression, the<unk> /ER complex is able to suppress the expression of the pro-proliferative ERBB2 protein. In contrast, when AIB-1 expression is higher than PAX2,<unk> /ER complex upregulates the expression of ERBB2 resulting in stimulation of breast cancer growth.<unk>  is antigonadotropic in postmenopausal women and partially suppresses levels of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in such women. However, it has progonadotropic effects in premenopausal women and increases estrogen levels by 6-fold in them. Due to the nature of<unk>  as a competitive ER ligand, this increase in estrogen levels is liable to interfere with the antiestrogenic efficacy of<unk> . The effects of<unk>  on breast cancer Ki-67 expression, sex hormone-binding globulin (SHBG) levels, and IGF-1 levels are dose-dependent across a dosage range of 1 to 20 mg/day in women with breast cancer.<unk>  has been found to decrease insulin-like growth factor 1 (IGF-1) levels by 17 to 38% in women and men. Suppression of IGF-1 production in the liver is a well-known action of estrogens and SERMs. A 10 mg/day dosage of<unk>  is nearly as effective as a 20 mg/day dosage in suppressing IGF-1 levels. Other activities Afimoxifene is an agonist of the G protein-coupled estrogen receptor (GPER) with relatively low affinity. Its affinity for the receptor is in the range of 100 to 1,000 nM, relative to 3 to 6 nM for estradiol. In addition to its activity as a SERM, afimoxifene binds to both the estrogen-related receptor β and estrogen-related receptor γ and is an antagonist of the estrogen-related receptor γ (ERRγ). Norendoxifen (4-hydroxy-N,N-didesmethyltamoxifen), another active metabolite of<unk> , has been found to act as a potent competitive aromatase inhibitor (IC50 = 90 nM), and may also be involved in the antiestrogenic activity of<unk> . In addition to its activity as a SERM,<unk>  is a potent and selective protein kinase C inhibitor, and is active in this regard at therapeutic concentrations. This action is thought to underlie the efficacy of<unk>  in the treatment of bipolar disorder.<unk>  is an inhibitor of P-glycoprotein. Pharmacokinetics Absorption<unk>  is rapidly and extensively absorbed from the intestines with oral administration. The oral bioavailability of<unk>  is approximately 100%, which is suggestive of minimal first-pass metabolism in the intestines and liver. Following intake, peak levels of<unk>  occur after three to seven hours. Steady state levels of<unk>  are reached typically after 3 to 4 weeks but possibly up to 16 weeks of daily administration. Steady state levels of afimoxifene are achieved after 8 weeks of daily<unk>  administration. Peak levels of<unk>  after a single 40 mg oral dose were 65 ng/mL and steady state levels at 20 mg/day were 310 ng/mL. Levels of<unk>  show clear dose dependency across a dosage range of 1 to 20 mg/day. Endoxifen levels are approximately 5 to 10 times higher than afimoxifene levels, with large interindividual variability. Endoxifen levels have been reported as 10.8 to 15.9 ng/mL at steady state in CYP2D6 normal metabolizers during therapy with 20 mg/day<unk> . The most abundant metabolites of<unk>  in terms of circulating concentrations are N-desmethyltamoxifen, N,N-didesmethyltamoxifen, (Z)-endoxifen, and<unk>  N-oxide. Distribution The volume of distribution of<unk>  is 50 to 60 L/kg and its clearance has been estimated as 1.2 to 5.1 L/hour. High concentrations of<unk>  have been found in breast, uterus, liver, kidney, lung, pancreas, and ovary tissue in animals and humans. Levels of<unk>  in the uterus have been found to be 2- to 3-fold higher than in the circulation and in the breasts 10-fold higher than in the circulation. The plasma protein binding of<unk>  and afimoxifene is greater than 99%. A majority of<unk>  is bound to albumin. Albumin alone binds 98.8% of<unk>  while other plasma proteins are not greatly involved. Metabolism<unk>  and its metabolites in humans Compound Mean plasmaconcentrations Effect on ER / affinity for ERa<unk>  190–420 nmol/L Weak antagonist / 2% N-Desmethyltamoxifen 280–800 nmol/L Weak antagonist / 1% N,N-Desmethyltamoxifen 90–120 nmol/L Weak antagonist Endoxifen 14–130 nmol/L Strong antagonist / equal to afimoxifene Afimoxifene 3–17 nmol/Lb Strong antagonist / 188% α-Hydroxytamoxifen 1 nmol/L None 3,4-Dihydroxytamoxifen ? Weak antagonist / high affinity<unk>  N-oxide 15–24 nmol/L Weak antagonistc Footnotes: a = Estradiol is 100%. b = One study reported a much higher concentration (67 nmol/L). c = Might be due to reduction to<unk> .<unk>  is a prodrug and is metabolized in the liver by the cytochrome P450 isoforms CYP3A4, CYP2C9, and CYP2D6 into active metabolites such as endoxifen (4-hydroxy-N-desmethyltamoxifen) and afimoxifene (4-hydroxytamoxifen). Conversion of<unk>  by N-demethylation into N-desmethyltamoxifen, which is catalyzed primarily by CYP3A4 and CYP3A5, is responsible for approximately 92% of<unk>  metabolism. Conversely, 4-hydroxylation of<unk>  into afimoxifene is responsible for only about 7% of<unk>  metabolism. Following its formation, N-desmethyltamoxifen is oxidized into several other metabolites, the most notable of which is endoxifen. Another active metabolite, norendoxifen (4-hydroxy-N,N-didesmethyltamoxifen), is formed via N-demethylation of endoxifen or 4-hydroxylation of N,N-didesmethyltamoxifen.<unk>  and its metabolites undergo conjugation, including glucuronidation and sulfation.<unk>  may inhibit its own metabolism. Elimination<unk>  has a long elimination half-life of typically 5 to 7 days, with a range of 4 to 11 days. Similarly, the half-life of afimoxifene is 14 days. Conversely, the half-life of endoxifen is 50 to 70 hours (2–3 days). The long half-lives of<unk>  and afimoxifene are attributed to their high plasma protein binding as well as to enterohepatic recirculation. Upon discontinuation of treatment, levels of<unk>  and its metabolites persist in the circulation for at least 6 weeks.<unk>  is excreted in bile and is eliminated in feces, while small amounts are eliminated in urine.
Tamoxifen
Endoxifen
N-Desmethyltamoxifen
Anastrozole
Salvestrol
Bazedoxifene
N,N-Didesmethyltamoxifen
Exemestane