Pharmacodynamics<unk>  acts as a potent and selective competitive antagonist of the gonadotropin-releasing hormone receptor (GnRHR), the biological target of the hypothalamic peptide hormone gonadotropin-releasing hormone (GnRH). As such, it is a GnRH antagonist. The affinity (KD) of<unk>  for the GnRHR is 54 pM. By blocking the GnRHR in the pituitary gland,<unk>  suppresses the GnRH-induced secretion of the gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the anterior pituitary, and thereby decreases the production of sex hormones by the gonads. In women,<unk>  dose-dependently suppresses the production of ovarian hormones including estradiol, progesterone, and testosterone, and thereby decreases the circulating levels of these hormones. In men, GnRH modulators suppress the testicular production of testosterone and estradiol, decreasing the circulating levels of these hormones similarly. Unlike previous GnRH agonists and antagonists, referred to collectively as GnRH analogues,<unk>  is a non-peptide and small-molecule compound that can be taken orally. Estrogens like estradiol stimulate the growth of the endometrium, and thereby aggravate symptoms of endometriosis. By suppressing estrogen production and levels,<unk>  decreases the growth of the endometrium and decreases endometriosis symptoms such as pelvic pain.<unk>  is a short-acting GnRH antagonist, with a terminal half-life of typically about 4 to 6 hours. Because of the short duration of<unk>  in the body, the activation of the GnRHR by GnRH is not fully blocked throughout the day with once-daily administration of<unk> . As a result, gonadotropin and sex hormone levels are only partially suppressed when<unk>  is taken once per day. In addition, the degree of suppression can be dose-dependently adjusted as needed, for instance with higher-dose twice-daily administration to achieve greater hormonal suppression. Because of its short duration in the body, the effects of<unk>  are rapidly reversible upon discontinuation. In addition, due to its partial and incomplete suppression of estradiol levels, the side effects of<unk> , such as hot flashes and decreased BMD, are lower than with first-generation GnRH modulators. In clinical trials,<unk>  produced dose-dependent decreases in gonadotropin, estradiol, and progesterone levels in women. Median levels of estradiol were partially suppressed to 42 pg/mL (follicular phase levels) with 150 mg once daily and were fully or near-fully suppressed to 12 pg/mL (postmenopausal levels) with 200 mg twice daily. In a 21-day study in premenopausal women, the effects of<unk>  on FSH levels were found to be maximal at a dosage of 300 mg twice per day or above, whereas its effects on LH and estradiol levels were maximal at a dosage of 200 mg twice per day or above. Levels of progesterone were maintained at anovulatory levels (C; SLCO1B1 521 C/C genotype), plasma levels of<unk>  have been found to be increased by 78% relative to in people with normal OATP1B1 function (SLCO1B1 521T/T genotype). The frequency of this reduced function OATP1B1 genotype is generally less than 5% in most racial and ethnic groups.<unk>  is excreted less than 3% in urine and 90% in feces. Exposure to<unk>  is not affected by renal impairment or mild hepatic impairment, but is increased by approximately 3-fold in women with moderate hepatic impairment and by approximately 7-fold in women with severe hepatic impairment. There were no differences in the pharmacokinetics of<unk>  between individuals of different racial and ethnic groups. Similarly, the pharmacokinetics of<unk>  were unaffected by body weight and body mass index. Peak and area-under-the-curve levels of<unk>  have been shown to be altered by CYP3A4 inhibitors like ketoconazole and CYP3A4 inducers like rifampin. Inhibitors of OATP1B1 may increase circulating levels of<unk> , and<unk>  is considered to be contraindicated in combination with strong OATP1B1 inhibitors.<unk>  is a substrate of P-glycoprotein, but the effect of inhibitors and inducers of P-glycoprotein on the pharmacokinetics of<unk>  is unknown.<unk>  itself is an inhibitor of P-glycoprotein.
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