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Tamoxifen Citrate, USP. Tamoxifen, 2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-A, A-dimethylethanamine (Nolvadex), is a triphenylethylene SERM used to treat early and advanced breast carcinoma in postmenopausal women. Tamoxifen is used as adjuvant treatment for breast cancer in women following mastectomy and breast irradiation. It reduces the occurrence of contralateral breast cancer in patients receiving adjuvant tamoxifen therapy. It is also effective in the treatment of metastatic breast cancer in both women and men. In premenopausal women with metastatic breast cancer, tamoxifen is an alternative to oophorectomy or ovarian irradiation. Tamoxifen can be used preventa-tively to reduce the incidence of breast cancer in women at high risk. Antiestrogenic and estrogenic side effects can include hot flashes, nausea, vomiting, platelet reduction, and (in patients with bone metastases) hypercalcemia. Like all triphenylethylene derivatives, it should be protected from light.

The major metabolite of tamoxifen is A -desmethyltamox-ifen, which reaches steady-state levels higher than tamoxifen itself. It is believed that A -desmethyltamoxifen contributes significantly to the overall antiestrogenic effect. Another metabolite, 4-hydroxytamoxifen, is a more potent antiestro-gen than tamoxifen, but because it is only a minor metabolite of tamoxifen, it probably does not contribute significantly to the therapeutic effects. 4-Hydroxytamoxifen, with its greater affinity for the ERs, however, has been used extensively in pharmacological studies of these receptors. Tamoxifen concentrations are reduced if coadministered with rifampin, a cytochrome P450 inducer.

Toremifene Citrate, USP. Toremifene, 2-[4-[(1Z)-4-chloro-1,2-diphenyl-1-butenyl]phenoxy]-N, N-di-methylethanamine (Fareston), differs structurally from tamoxifen only by having a chloroethyl group (rather than an ethyl group) attached to the triphenylethylene structure. As might be expected, the pharmacological actions of toremifene and tamoxifen are quite similar. Toremifene is also a SERM, with estrogen antagonist action in breast tissue but agonist action in the endometrium, on bone tissue, and on serum lipid profiles. Recent clinical data indicate that the incidence of endometrial cancer is lower with toremifene use than with ta-moxifen.62 Toremifene is used in the treatment of metastatic breast cancer in postmenopausal women.

Raloxifene, USP. Raloxifene, [6-hydroxy-2-(4-hy-droxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl) ethoxy]phenyl]methanone (Evista), is a benzothiophene derivative that differs slightly from the triphenylethylene SERMs. A key structural difference is the carbonyl "hinge" that connects the modified phenolic side chain to the ben-zothiophene ring system. This hinge is the key structural element that leads to the differing actions at the ERs.55 Raloxifene, unlike tamoxifen and toremifene, has antagonist properties on the endometrium and breast tissue and agonist properties on bone and the cardiovascular system. The lack of agonist action on endometrial tissue has been suggested as a reason for the lack of endometrial cancer associated with raloxifene use. Raloxifene is approved for the prevention and treatment of osteoporosis in postmenopausal women. It has also been investigated for preventing breast cancer in comparison with tamoxifen. Recent studies indicates that it has similar effectiveness to tamoxifen, but has a preferable side effect profile.63

Bazedoxifene, USP. Bazedoxifene, 1-[[4-[2-(azepan-1-yl)ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methyl-indol-5-ol (Viviant), was declared to be "approvable" by the FDA in 2007 for the prevention of postmenopausal osteoporosis. As of mid-2009, final approval in the United States is still pending. Bazedoxifene was approved in Europe in 2009 for the treatment of post-menopausal osteoporosis.

Fulvestrant, USP. Fulvestrant, 7«-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-triene-3, 17^-diol (Faslodex), is an antagonist structurally based on the estradiol structure, with a long, substituted alkyl chain attached at the 7a-position of the steroid skeleton. When bound to the ERs, this alkyl chain induces a conformation of the receptor distinctive from that formed upon estradiol or tamoxifen binding, preventing agonist action. Fulvestrant is a pure antagonist at both ERa and ER^ and an ER downregulator (stimulates degradation of the ER), completely lacking the agonist activity that is seen with ta-moxifen or raloxifene. The different pharmacological profile of fulvestrant allows the use of this agent in women who have had disease progression after prior antiestrogen therapy (typically tamoxifen), providing an alternative to aromatase inhibitors.64

Figure 25.16 • Conversion of androstenedione to estrone by aromatase.

Clomiphene Citrate, USP. Clomiphene citrate, 2-[4(2-chloro-1,2-diphenylethenyl)phenoxy]-N, N -diethyl-ethanamine (Clomid), is used as an ovulation stimulant in women desiring pregnancy. Although early literature refers to clomiphene as an estrogen antagonist, it is more accurately a SERM.65 Clomiphene is chemically a mixture of two geometric isomers, zuclomiphene, the cis-isomer, and en-clomiphene, the trans-isomer. In animal studies, these isomers have different estrogenic actions in different tissues. Zuclomiphene appears to have weak agonist actions on all tissues studied, whereas enclomiphene has antagonist actions on uterine tissue, but agonist action on bone tissue.66 The actions of clomiphene in humans are likely a composite of the actions of the two isomers.

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