by the enzyme 24-dehydrocholesterol reductase. concerns about possible induction of desmosterolosis and associated symptoms such as cataracts and ichthyosis with extended exposure precluded the use of clomifene in the treatment of breast cancer. continuous use of clomifene has been found to increase desmosterol levels by 10% and continuous high doses of clomifene (200 mg/day) have been reported to produce visual disturbances. pharmacokinetics clomifene produces n-desmethylclomifene, clomifenoxide (clomifene n-oxide), 4-hydroxyclomifene, and 4-hydroxy-n-desmethylclomifene as metabolites. clomifene is a prodrug most importantly of 4-hydroxyclomifene and 4-hydroxy-n-desmethylclomifene, which are the most active of its metabolites. in one study, the peak levels after a single 50 mg dose of clomifene were 20.37 nmol/l for clomifene, 0.95 nmol/l for 4-hydroxyclomifene, and 1.15 nmol/l for 4-hydroxy-n-desmethylclomifene. clomifene has an onset of action of 5 to 10 days following course of treatment and an elimination half-life about 4 - 7days. in one study, after a single 50 mg dose of clomifene, the half-life of clomifene was 128 hours (5.3 days), of 4-hydroxyclomifene was 13 hours, and of 4-hydroxy-n-desmethylclomifene was 15 hours. individuals with the cyp2d6*10 allele showed longer half-lives for 4-hydroxyclomifene and 4-hydroxy-n-desmethylclomifene. primarily due to differences in cyp2d6 genetics, steady state concentrations and individual response to clomifene are highly variable. most clomifene metabolism occurs in the liver, where it undergoes enterohepatic recirculation. clomifene and its metabolites are excreted primarily through feces (42%), and excretion can occur up to 6 weeks after discontinuation. chemistry clomifene is a triphenylethylene derivative. it is a mixture of two geometric isomers, the cis enclomifene ((e)-clomifene) form and trans zuclomifene ((z)-clomifene) form. these two isomers contribute to the mixed estrogenic and antiestrogenic properties of clomifene. the typical ratio of these isomers after synthesis is 38% zuclomiphene and 62% enclomiphene. the united states pharmacopeia specifies that clomifene preparations must contain between 30% and 50% zuclomiphene. enclomifene zuclomifene history a team at william s. merrell chemical company led by frank palopoli synthesized clomifene in 1956; after its biological activity was confirmed a patent was filed and issued in november 1959. scientists at merrell had previously synthesized chlorotrianisene and ethamoxytriphetol. clomifene was studied in the treatment of advanced breast cancer during the period of 1964 to 1974 and was found to be effective but was abandoned due to concerns about desmosterolosis with extended use. short-term use (e.g. days to months) did not raise the same concerns and clomifene continued to be studied for other indications. comparison of early clinical experience with antiestrogens for advanced breast cancer antiestrogen dosage year(s) response rate toxicity ethamoxytriphetol 500–4,500 mg/day 1960 25% acute psychotic episodes clomifene 100–300 mg/day 1964–1974 34% fears of cataracts nafoxidine 180–240 mg/day 1976 31% cataracts, ichthyosis, photophobia tamoxifen 20–40 mg/day 1971–1973 31% transient thrombocytopeniaa footnotes: a = "the particular advantage of this drug is the low incidence of troublesome side effects (25)." "side effects were usually trivial (26)." sources: clinical studies were conducted under an investigational new drug application; clomifene was third drug for which an ind had been filed under the 1962 kefauver harris amendment to the federal food, drug, and cosmetic act that had been passed in response to the thalidomide tragedy. it was approved for marketing in 1967 under the brand name clomid. it was first used to treat cases of oligomenorrhea but was expanded to include treatment of anovulation when women undergoing treatment had higher than expected rates of pregnancy. the drug is widely considered to have been a revolution in the treatment of female infertility, the beginning of the modern era of assisted reproductive technology, and the beginning of what in the words of eli y. adashi, was "the onset of the us multiple births epidemic". the company was acquired by dow chemical in 1980, and in 1989 dow chemical acquired 67 percent interest of marion laboratories, which was renamed marion merrell dow. in 1995 hoechst ag acquired the pharmaceutical business of marion merrell dow. hoechst in turn became part of aventis in 1999,: 9–11 and subsequently a part of sanofi. it became the most widely prescribed drug for ovulation induction to reverse anovulation or oligoovulation. society and culture brand names clomifene is marketed under many brand names worldwide, including beclom, bemot, biogen, blesifen, chloramiphene, clofert, clomene, clomhexal, clomi, clomid, clomidac, clomifen, clomifencitrat, clomifene, clomifène, clomifene citrate, clomifeni citras, clomifeno, clomifert, clomihexal, clomiphen, clomiphene, clomiphene citrate, cloninn, clostil, clostilbegyt, clovertil, clovul, dipthen, dufine, duinum, fensipros, fertab, fertec, fertex, ferticlo, fertil, fertilan, fertilphen, fertin, fertomid, ferton, fertotab, fertyl, fetrop, folistim, genoclom, genozym, hete, i-clom, ikaclomin, klofit, klomen, klomifen, lomifen, mer 41, milophene, ofertil, omifin, ova-mit, ovamit, ovinum, ovipreg, ovofar, ovuclon, ovulet, pergotime, pinfetil, profertil, prolifen, provula, reomen, serofene, serophene, serpafar, serpafar, surole, tocofeno, and zimaquin. regulation clomifene is included on the world anti-doping agency list of illegal doping agents in sport. it is listed because it is an "anti-estrogenic substance". research clomifene has been used almost exclusively for ovulation induction in premenopausal women, and has been studied very limitedly in postmenopausal women. clomifene was studied for treatment and prevention of breast cancer, but issues with toxicity led to abandonment of this indication, as did the discovery of tamoxifen. like the structurally related drug triparanol, clomifene is known to inhibit the enzyme 24-dehydrocholesterol reductase and increase circulating desmosterol levels, making it unfavorable for extended use in breast cancer due to risk of side effects like irreversible cataracts.