Pharmacodynamics Antiandrogenic activity<unk>  acts as a highly selective competitive silent antagonist of the ( = 159–243 nM), the major biological target of the androgen sex hormones testosterone and , and hence is an antiandrogen. The activity of<unk>  lies in the (R)-isomer. Due to its selectivity for the ,<unk>  does not interact importantly with other steroid hormone receptors and hence has no clinically relevant off-target hormonal activity (e.g., progestogenic, estrogenic, glucocorticoid, antimineralocorticoid). However, it has been reported that<unk>  has weak affinity for the progesterone receptor (PR), where it is an antagonist, and hence it could have some antiprogestogenic activity.<unk>  does not inhibit 5α-reductase nor is known to inhibit other enzymes involved in androgen steroidogenesis (e.g., CYP17A1). Although it does not bind to the estrogen receptors (ERs),<unk>  can increase estrogen levels secondarily to blockade when used as a monotherapy in males, and hence can have some indirect estrogenic effects in males.<unk>  neither suppresses nor inhibits androgen production in the body (i.e., it does not act as an antigonadotropin or androgen steroidogenesis inhibitor or lower androgen levels) and hence exclusively mediates its antiandrogenic effects by antagonizing the . In addition to the classical nuclear ,<unk>  has been assessed at the membrane androgen receptors (mARs) and found to act as a potent antagonist of ZIP9 ( = 66.3 nM), whereas it does not appear to interact with GPRC6A. The affinity of<unk>  for the is relatively low as it is approximately 30 to 100 times lower than that of , which is 2.5- to 10-fold as potent as an agonist as testosterone in bioassays and is the main endogenous ligand of the receptor in the prostate gland. However, typical clinical dosages of<unk>  result in circulating levels of the drug that are thousands of times higher than those of testosterone and , allowing it to powerfully prevent them from binding to and activating the receptor. This is especially true in the case of surgical or medical castration, in which testosterone levels in the circulation are approximately 95% reduced and levels in the prostate gland are about 50 to 60% reduced. In women, levels of testosterone are substantially lower (20- to 40-fold) than in men, so much smaller doses of<unk>  (e.g., 25 mg/day in the hirsutism studies) are necessary. Blockade of the by<unk>  in the pituitary gland and hypothalamus results in prevention of the negative feedback of androgens on the hypothalamic–pituitary–gonadal axis (HPG axis) in males and consequent disinhibition of pituitary luteinizing hormone (LH) secretion. This, in turn, results in an increase in circulating levels and activation of the gonadal production of testosterone and by extension production of estradiol. Levels of testosterone have been found to increase 1.5- to 2-fold (59–97% increase) and levels of estradiol about 1.5- to 2.5-fold (65–146% increase) in men treated with 150 mg/day<unk>  monotherapy. In addition to testosterone and estradiol, there are smaller increases in concentrations of , sex hormone-binding globulin, and prolactin. Estradiol levels with<unk>  monotherapy are similar to those in the low-normal premenopausal female range while testosterone levels generally remain in the high end of the normal male range. Testosterone concentrations do not typically exceed the normal male range due to negative feedback on the axis by the increased concentrations of estradiol.<unk>  influences the axis and increases hormone levels only in men and not also in women. This is due to the much lower levels of androgens in women and their lack of basal suppression of the axis in this sex. As evidenced by its effectiveness in the treatment of prostate cancer and other androgen-dependent conditions, the antiandrogenic actions of<unk>  considerably exceed any impact of the increased levels of testosterone it results in. However, the elevated levels of estradiol remain unopposed by<unk>  and are responsible for the gynecomastia and feminizing side effects it causes in men. Although<unk>  monotherapy increases gonadotropin and sex hormone levels in men, this will not occur if<unk>  is combined with an antigonadotropin such as a analogue, estrogen, or progestogen, as these medications maintain negative feedback on the HPG axis. monotherapy, including with<unk> , shows a number of tolerability differences from methods of androgen deprivation therapy that incorporate surgical or medical castration. For example, the rates of hot flashes, depression, fatigue, and sexual dysfunction are all much higher with analogues than with monotherapy. It is thought that this is because analogues suppress estrogen production in addition to androgen production, resulting in estrogen deficiency. In contrast, monotherapy does not decrease estrogen levels and in fact increases them, resulting in an excess of estrogens that compensates for androgen deficiency and allows for a preservation of mood, energy, and sexual function. Neurosteroids that are produced from testosterone like 3α-androstanediol and 3β-androstanediol, which are agonists and the former a potent GABAA receptor positive allosteric modulator, may also be involved. In the specific case of sexual dysfunction, an additional possibility for the difference is that without concomitant suppression of androgen production, blockade of the by the<unk>  in the brain is incomplete and insufficient to markedly influence sexual function. Under normal circumstances,<unk>  has no capacity to activate the . However, in prostate cancer, mutations and overexpression of the can accumulate in prostate gland cells which can convert<unk>  from an antagonist of the into an agonist. This can result in paradoxical stimulation of prostate cancer growth with<unk>  and is responsible for the phenomenon of the antiandrogen withdrawal syndrome, where antiandrogen discontinuation paradoxically slows the rate of prostate cancer growth. In transgender women, breast development is a desired effect of antiandrogen or estrogen treatment. Breast development and gynecomastia induced by<unk>  is thought to be mediated by increased activation of the secondary to blockade of the (resulting in disinhibition of the in breast tissue) and increased levels of estradiol. In addition to fat deposition, connective tissue growth, and ductal development,<unk>  has been found to produce moderate lobuloalveolar development of the breasts. However, full lobuloalveolar maturation necessary for lactation and breastfeeding will not occur without progestogen treatment.<unk>  monotherapy seems to have minimal effect on testicular spermatogenesis, testicular ultrastructure, and certain aspects of male fertility. This seems to be because testosterone levels in the testes (where ≈95% of testosterone in males is produced) are extremely high (up to 200-fold higher than circulating levels) and only a small fraction (less than 10%) of the normal levels of testosterone in the testes are actually necessary to maintain spermatogenesis. As a result,<unk>  appears to not be able to compete with testosterone in this sole part of the body to an extent sufficient to considerably interfere with androgen signaling and function. However, while<unk>  does not seem to be able to adversely influence testicular spermatogenesis, it may interfere with -dependent sperm maturation and transport outside of the testes in the epididymides and vas deferens where androgen levels are far lower, and hence may still be able to impair male fertility. In addition, the combination of<unk>  with other medications, such as estrogens, progestogens, and analogues, can compromise spermatogenesis due to their own adverse effects on male fertility. These medications are able to strongly suppress gonadal androgen production, which can severely impair or abolish testicular spermatogenesis, and estrogens also appear to have direct and potentially long-lasting cytotoxic effects in the testes at sufficiently high concentrations. Other activities<unk>  has been found to act as an inhibitor or inducer of certain cytochrome P450 enzymes including CYP3A4, CYP2C9, CYP2C19, and CYP2D6 in preclinical research, but no evidence of this has been found in humans treated with up to 150 mg/day. It has also been identified in vitro as a strong inhibitor of CYP27A1 (cholesterol 27-hydroxylase) and as an inhibitor of CYP46A1 (cholesterol 24-hydroxylase), but this has yet to be assessed or confirmed in vivo or in humans and the clinical significance remains unknown.<unk>  has been found to be a P-glycoprotein (ABCB1) inhibitor. Like other first-generation and enzalutamide, it has been found to act as a weak non-competitive inhibitor of GABAA receptor-mediated currents in vitro ( = 5.2 μM). However, unlike enzalutamide,<unk>  has not been found to be associated with seizures or other related adverse central effects, so the clinical relevance of this finding is uncertain. Pharmacokinetics Though its absolute bioavailability in humans is unknown,<unk>  is known to be extensively and well-absorbed. Its absorption is not affected by food. The absorption of<unk>  is linear at doses up to 150 mg/day and is saturable at doses above this, with no further increases in steady-state levels of<unk>  occurring at doses above 300 mg/day. Whereas absorption of (R)-bicalutamide is slow, with levels peaking at 31 to 39 hours after a dose, (S)-bicalutamide is much more rapidly absorbed. Steady-state concentrations of the drug are reached after 4 to 12 weeks of treatment independently of dosage, with a 10- to 20-fold progressive accumulation in levels of (R)-bicalutamide. The long time to steady-state levels is the result of<unk> 's very long elimination half-life. The tissue distribution of<unk>  is not
Bicalutamide
Darolutamide
Topilutamide
Apalutamide
Nilutamide
Acetothiolutamide
Flutamide
Enzalutamide