Pharmacodynamics Estradiol levels with 40 mg<unk>  once per day in premenopausal women relative to untreated premenopausal women.<unk>  is a selective antagonist of the gonadotropin-releasing hormone receptor (GnRHR), with a half-maximal inhibitory concentration (IC50) of 0.12 nM. A dosage of<unk>  of 40 mg once per day has been found to suppress estradiol levels to postmenopausal levels (<20 pg/mL) within 24 hours in premenopausal women. In the control group of women, estradiol levels fluctuated between 50 and 250 pg/mL. Estradiol levels have been found to return to normal concentrations within 4 weeks of discontinuation of<unk>  in premenopausal women. The medication additionally suppresses levels of progesterone, luteinizing hormone, and follicle-stimulating hormone in premenopausal women.<unk>  at a dosage of 40 mg or more once per day has been found to reduce testosterone levels to sustained castrate levels (<20 ng/dL) in men. It additionally suppresses luteinizing hormone and follicle-stimulating hormone levels in men. Lower doses of<unk>  (<40 mg/day) are under investigation for achieving partial sex hormone suppression in the treatment of endometriosis and uterine fibroids. This is intended to reduce the incidence and severity of menopausal symptoms such as hot flushes and decreased bone mineral density that are secondary to estrogen deficiency. Pharmacokinetics A single 40-mg oral dose of<unk>  has been found to result in peak levels of<unk>  of 29 ng/mL (47 nmol/L) after 1.5 hours. Steady-state levels are reached within 7 days with 40 mg/day<unk>  administration. There is an approximate 2-fold accumulation of<unk>  by 2 weeks of continuous administration. Food diminishes the oral bioavailability of<unk>  by about 50%.<unk>  is a substrate for P-glycoprotein, which may have a limiting effect on its absorption and distribution. The plasma protein binding of<unk>  is approximately 68 to 71% over a concentration range of 0.05 to 5 μg/mL.<unk>  is not a substrate for CYP3A4. The elimination half-life of<unk>  is 36 to 65 hours across a dosage range of 20 to 180 mg/day. There is moderate to high interindividual variability in systemic exposure to<unk> .<unk>  is excreted mainly in feces (83%) and to a small degree in urine (4%). Only about 6% of a dose of<unk>  is excreted unchanged.
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