Pharmacodynamics Antiandrogenic activity Bicalutamide 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 bicalutamide lies in the (
R)-isomer. However, it has been reported that bicalutamide has weak affinity for the
progesterone receptor (PR), where it is an antagonist, and hence it could have some
antiprogestogenic activity. Bicalutamide does not
inhibit 5α-reductase nor is known to inhibit other
enzymes involved in androgen
steroidogenesis (e.g.,
CYP17A1). Bicalutamide 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 . The
affinity of bicalutamide 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 bicalutamide 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 bicalutamide (e.g., 25 mg/day in the hirsutism studies) are necessary. 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 bicalutamide monotherapy. In addition to testosterone and estradiol, there are smaller increases in concentrations of ,
sex hormone-binding globulin, and
prolactin. This is due to the much lower levels of androgens in women and their lack of basal suppression of the axis in this sex. Although bicalutamide monotherapy increases gonadotropin and sex hormone levels in men, this will not occur if bicalutamide 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 bicalutamide, 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. 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 bicalutamide in the brain is incomplete and insufficient to markedly influence sexual function. Under normal circumstances, bicalutamide has no capacity to activate the . However, in prostate cancer,
mutations and overexpression of the can accumulate in prostate gland cells which can convert bicalutamide from an antagonist of the into an
agonist. This can result in paradoxical stimulation of prostate cancer growth with bicalutamide and is responsible for the phenomenon of the
antiandrogen withdrawal syndrome, where antiandrogen discontinuation paradoxically slows the rate of prostate cancer growth. Breast development and gynecomastia induced by bicalutamide 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, bicalutamide 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. 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, bicalutamide 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. In addition, the combination of bicalutamide 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. Bicalutamide 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, bicalutamide has not been found to be associated with
seizures or other related adverse
central effects, so the clinical relevance of this finding is uncertain. 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. The long time to steady-state levels is the result of bicalutamide's very long
elimination half-life. The amount of bicalutamide in
semen that could potentially be transferred to a female partner during
sexual intercourse is low and is not thought to be important. As such, it was initially thought to be a
peripherally selective antiandrogen. In any case, there is indication that bicalutamide might have at least some peripheral selectivity in humans. Bicalutamide is highly
plasma protein bound (96.1% for racemic bicalutamide, 99.6% for (
R)-bicalutamide) and is bound mainly to
albumin, with negligible binding to and
corticosteroid-binding globulin. Bicalutamide is
metabolized in the
liver. (
R)-Bicalutamide has a relatively long elimination half-life of 5.8 days with a single dose and 7 to 10 days following repeated administration. Bicalutamide is
eliminated in similar proportions in
feces (43%) and
urine (34%), while its metabolites are eliminated roughly equally in
urine and
bile. The drug is
excreted to a substantial extent in unmetabolized form, and both bicalutamide and its metabolites are eliminated mainly as
glucuronide conjugates. The pharmacokinetics of bicalutamide are not affected by consumption of food, a person's age or body weight,
renal impairment, or mild-to-moderate
hepatic impairment. However, steady-state levels of bicalutamide are higher in
Japanese individuals than in
white people. ==Chemistry==