toremifene toremifene toremifene, sold under the brand name fareston among others, is a medication which is used in the treatment of advanced breast cancer in postmenopausal women. it is taken by mouth. toremifeneclinical datapronunciation/ˈtɔːrəmɪfiːn/ trade namesfareston, othersother names(z)-toremifene; 4-chlorotamoxifen; 4-ct; acapodene; ccris-8745; fc-1157; fc-1157a; gtx-006; nk-622; nsc-613680ahfs/drugs.commonographmedlineplusa608003license data eu ema: by inn routes ofadministrationby mouthdrug classselective estrogen receptor modulatoratc codel02ba02 (who) pharmacokinetic databioavailabilitygood/~100%protein binding99.7%metabolismliver (cyp3a4)metabolitesn-desmethyltoremifene; 4-hydroxytoremifene; ospemifeneelimination half-lifetoremifene: 3–7 daysmetabolites: 4–21 daysexcretionfeces: 70% (as metabolites)identifiers iupac name 2-phenoxy]-n,n-dimethylethanamine cas number89778-26-7 y 89778-27-8 (citrate)pubchem cid3005573iuphar/bps4325drugbankdb00539 ychemspider2275722 yunii7nfe54o27tkeggd08620 ychebichebi:9635 ychemblchembl1655 ypdb ligandt0r (pdbe, rcsb pdb)comptox dashboard (epa)dtxsid3023689 echa infocard100.125.139 chemical and physical dataformulac26h28clnomolar mass405.97 g·mol−13d model (jsmol)interactive image smiles clccc(/c1ccccc1)=c(/c2ccc(occn(c)c)cc2)c3ccccc3 inchi inchi=1s/c26h28clno/c1-28(2)19-20-29-24-15-13-23(14-16-24)26(22-11-7-4-8-12-22)25(17-18-27)21-9-5-3-6-10-21/h3-16h,17-20h2,1-2h3/b26-25- ykey:xfcljvaboiyomf-qplcgjkrsa-n y (verify) side effects of toremifene include hot flashes, sweating, nausea, vomiting, dizziness, vaginal discharge, and vaginal bleeding. it can also cause blood clots, irregular heartbeat, cataracts, visual disturbances, elevated liver enzymes, endometrial hyperplasia, and endometrial cancer. high blood calcium levels can occur in women with bone metastases. the medication is a selective estrogen receptor modulator (serm) and hence is a mixed agonist–antagonist of the estrogen receptor (er), the biological target of estrogens like estradiol. it has estrogenic effects in bone, the liver, and the uterus and antiestrogenic effects in the breasts. it is a triphenylethylene derivative and is closely related to tamoxifen. toremifene was introduced for medical use in 1997. it was the first antiestrogen to be introduced since tamoxifen in 1978. it is available as a generic medication in the united states. medical uses toremifene is approved for the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor-positive or unknown-status tumors. this is its only approved use in the united states. it shows equivalent effectiveness to tamoxifen for this indication. toremifene has been found to be effective in the treatment of breast pain and may be a more effective medication than tamoxifen for this indication. it also has superior effects on bone mineral density and lipid profile, including levels of cholesterol and triglycerides, compared to tamoxifen. toremifene has been reported to significantly improve symptoms of gynecomastia in men. available forms toremifene is provided in the form of 60 mg oral tablets. side effects the side effects of toremifene are similar to those of tamoxifen. the most common side effect is hot flashes. other side effects include sweating, nausea, vomiting, dizziness, vaginal discharge, and vaginal bleeding. in women with bone metastases, hypercalcemia may occur. toremifene has a small risk of thromboembolic events. cataracts, vision changes, and elevation of liver enzymes have been reported. the drug prolongs the qt interval and hence has a risk of potentially fatal dysrhythmias. the risk of dysrhythmias can be reduced by avoiding use in patients with hypokalemia, hypomagnesemia, pre-existing qt prolongation, and in those taking other qt-prolonging drugs. because toremifene has estrogenic actions in the uterus, it can increase the risk of endometrial hyperplasia and endometrial cancer. toremifene appears to be safer than tamoxifen. it has a lower risk of venous thromboembolism (vte) (e.g., pulmonary embolism), stroke, and cataracts. the lower risk of vte may be related to the fact tamoxifen decreases levels of the antithrombin iii to a significantly greater extent than either 60 or 200 mg/day toremifene. interactions toremifene is a substrate of cyp3a4, a cytochrome p450 enzyme, and hence drugs that induce or inhibit this enzyme can respectively decrease or increase levels of toremifene in the body. pharmacology pharmacodynamics toremifene 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. tissue-specific estrogenic and antiestrogenic activity of serms medicationbreastboneliveruterusvaginabrain lipidscoagulationshbgigf-1hot flashesgonadotropins estradiol++++++++++ "ideal serm"–++±±±–++± bazedoxifene–++++ ?–±– ? clomifene–++ ?++– ?–± lasofoxifene–+++ ? ?±±– ? ospemifene–+++++±±–± raloxifene–+++++±––± tamoxifen–++++++––± toremifene–++++++––± effect: + = estrogenic / agonistic. ± = mixed or neutral. – = antiestrogenic / antagonistic. note: serms generally increase gonadotropin levels in hypogonadal and eugonadal men as well as premenopausal women (antiestrogenic) but decrease gonadotropin levels in postmenopausal women (estrogenic). sources: see template. the affinity of toremifene for the er is similar to that of tamoxifen. in studies using rat er, toremifene had about 1.4% and tamoxifen had about 1.6% of the affinity of estradiol for the er. the affinities (ki) of toremifene 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, toremifene 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 toremifene 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 toremifene, particularly 4-hydroxytoremifene, may contribute importantly to the clinical activity of the medication. on the other hand, some authorities consider toremifene not to be a prodrug. toremifene is very similar to tamoxifen and shares most of its properties. there are some indications that toremifene 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 toremifene and tamoxifen, including in terms of effectiveness, tolerability, and safety, and hence the clinical use of toremifene has been somewhat limited. toremifene is thought to have about one-third of the potency of tamoxifen; i.e., 60 mg toremifene is roughly equivalent to 20 mg tamoxifen in the treatment of breast cancer. toremifene 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). absorption the bioavailability of toremifene has not been precisely determined but is known to be good and has been estimated to be approximately 100%. levels of toremifene at steady state with a dosage of 60 mg/day are 800 to 879 ng/ml. levels of n-desmethyltoremifene at steady state with toremifene 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 toremifene were 438 ng/ml at 200 mg/day and 889 ng/ml at 400 mg/day. concentrations of toremifene increase linearly across a dose range of 10 to 680 mg. distribution toremifene 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 toremifene ranged from 457 to 958 l. metabolism toremifene is metabolized in the liver primarily by cyp3a4 and then undergoes secondary hydroxylation. the metabolites of toremifene include n-desmethyltoremifene, 4-hydroxytoremifene, and 4-hydroxy-n-desmethyltoremifene, among others. ospemifene (deaminohydroxytoremifene) is also a major metabolite of toremifene. elimination the elimination half-life of toremifene 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 toremifene are 5 to 21 days for n-desmethyltoremifene, 5 days for 4-hydroxytoremifene, and 4 days for ospemifene. the long elimination half-lives of toremifene and its metabolites are thought to be due to enterohepatic recirculation and high plasma protein binding. toremifene is eliminated 70% in the feces, as metabolites. chemistry