Antiandrogens Bicalutamide Flutamide and Nilutamide

The antiandrogens block androgen receptors to inhibit the action of testosterone and dihydrotestosterone in prostate cancer cells. Unfortunately, prostate cancer cells may become hormone refractory.

Flutamide is an androgen receptor antagonist that achieves peak concentrations ap-proximatley 2 to 4 hours after an oral dose. Flutamide is metabolized extensively, with a terminal half-life of about 8 hours. Bicalutamide achieves peak concentrations approximately 6 hours after the dose, with a terminal half-life of 6 to 10 days. Bicalutamide undergoes stereospecific metabolism, where the ^-enantiomer is cleared more rapidly by the liver than the ^-enantiomer. Nilutamide achieves peak serum concentrations between 1 and 4 hours after an oral dose and has a terminal halflife of 38 to 60 hours. Nilutamide is metabolized extensively, with less than 2% excreted as unchanged drug by the kidney. Side effects common to these agents are hot flashes, gynecomastia, and decreased libido. Flutamide tends to be associated with more diarrhea and requires three-times-daily administration, whereas bicalutamide is dosed once daily. Nilutamide may cause interstitial pneumonia and is associated with the visual disturbance of delayed adaptation to darkness.

Luteinizing Hormone—Releasing Hormone Agonists: Goserelin and Leuprolide

Initially, luteinizing hormone-releasing hormone (LHRH) agonists increase levels of leutinizing hormone and follicle-stimulating hormone, but testosterone and estrogen levels are decreased because of continuous negative-feedback inhibition. Major side effects are testicular atrophy, decreased libido, gynecomastia, and hot flashes. Leuprolide is well absorbed, with a terminal half-life of 2.9 hours, whereas goserelin has a terminal half-life of 4.9 hours. Goserelin is injected as a pellet under the skin, so subcutaneous injection of lidocaine prior to administration helps to decrease the pain associated with goserelin administration. Numerous dosage forms are available for leuprolide with varying strengths and dosing intervals. Antiandrogens may be administered during initial therapy to decrease symptoms of tumor flare (e.g., bone pain and urinary tract obstruction).


While ketoconazole is an antifungal agent, it has been used for treatment of prostate cancer. In high doses of 400 mg three times daily, ketoconazole blocks the production of testosterone.

LHRH Antagonist: Abarelix

Abarelix is a gonadotropin-releasing hormone antagonist that is associated with life-threatening hypersensitivity reactions. Patients must be observed for 30 minutes after administration. The drug is limited to men who cannot risk tumor flare and refuse orchiectomy.


Aminoglutethimide blocks the conversion of androgens to estrogens and decreases the synthesis of glucocorticoids. Adrenocorticoid suppression may occur, so replacement therapy with hydrocortisone may be required. Other side effects include rash (which usually resolves in 5-8 days), lethargy, and anorexia.


Anastrozole is a selective nonsteroidal aromatase inhibitor that lowers estrogen levels. The pharmacokinetics of anastrozole demonstrate good absorption, with hepatic metabolism the primary route of elimination and only 10% excreted unchanged by the kidney. The elimination half-life is approximately 50 hours. Anastrozole is used for the adjuvant treatment of postmenopausal women with hormone-positive breast cancer and in breast cancer patients who have had disease progression following tamoxifen. Side effects include hot flashes, arthralgias, osteoporosis/bone fractures, and thrombophlebitis.


Exemestane is an irreversible aromatase inactivator that binds to the aromatase enzyme to block the production of estrogen from androgens. Exemestane is absorbed rapidly after oral administration, with a terminal half-life of 24 hours. The drug is eliminated primarily by the liver and feces, with less than 1% of the dose excreted unchanged in the urine. Exemestane is indicated for the treatment of advanced breast cancer in postmenopausal women who have had disease progression following tamoxifen therapy. Side effects include hot flashes, fatigue, osteoporosis/bone fractures, and flu-like symptoms.


Fulvestrant is an estrogen receptor antagonist that binds to the estrogen receptor and is given as a monthly intramuscular injection. Fulvestrant has a terminal half-life of 40 days and a large volume of distribution of 3 to 5 L/kg. Fulvestrant is metabolized primarily, with excretion primarily via feces. Fulvestrant is used for the treatment of hormone-receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. Side effects are hot flashes, abdominal pain, depression, and myalgias.


Letrozole is another selective aromatase that inhibits the conversion of androgens to estrogen. Maximum plasma concentrations occur 1 hour after oral dosing; concomitant food has not been shown to have an effect on the extent of absorption of letrozole. The terminal half-life is approximately 2 days. Letrozole is used in the treatment of postmenopausal women with hormone-receptor-positive or unknown advanced breast cancer. Side effects include bone pain, hot flushes, back pain, nausea, arthralgia, osteoporosis/bone fractures, and dyspnea.

Megestrol Acetate

Megestrol is a synthetic progestin with antiestrogen properties that is used for breast cancer and in higher doses for weight gain. Side effects include fluid retention, hot flashes, vaginal bleeding and spotting, breast tenderness, and thrombosis.


Tamoxifen is an estrogen receptor antagonist. Most of a dose of tamoxifen is eliminated primarily by metabolism, with significant enterohepatic recirculation. The time to a peak concentration is 6 hours after an oral dose, and the terminal half-life is 7 days. Tamoxifen is used primarily for the treatment of postmenopausal hormone-receptor-positive breast cancer patients and the prevention of breast cancer in postmenopaus-al women. Side effects include hot flashes, fluid retention, mood swings, thrombosis, endometrial and uterine cancer, and corneal changes and cataracts. Since tamoxifen is a substrate of CYP450 3A4, decreased tamoxifen levels have occurred with use of St. John's wort, and decreased tamoxifen levels have been observed with use of rifampin. Tamoxifen is also a substrate for CYP450 2D6, and recent evidence suggests that those who are CYP2D6*4/*4 may have a poorer response and more toxicity with 47

tamoxifen. Significant drug interactions exist with antidepressants which may be used to treat depression or help relieve hot flashes.


Toremifene is an estrogen receptor antagonist. The pharmacokinetics of toremifene are best described by a two-compartment model, with an a-half-life of 4 hours and an elimination half-life of 5 days. Peak plasma concentrations are achieved approximately 3 hours after an oral dose. Toremifene is metabolized extensively, with metabolites found primarily in the feces. Toremifene is used for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor-positive or unknown tumors. Toremifene causes hot flashes, vaginal bleeding, thromboembolism, and visual acuity changes.

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