that it is likely that systemic bicalutamide therapy is unable to achieve concentrations of the drug within the testes that are able to considerably block androgen signaling in this part of the body. this is particularly so considering that bicalutamide increases circulating testosterone levels, and by extension gonadal testosterone production, by up to two-fold in males, and that only a small fraction of normal intratesticular testosterone levels, and by extension androgen action, appears to be necessary to maintain spermatogenesis. bicalutamide monotherapy at 50 mg/day causes no or clinically unimportant leydig cell hyperplasia. in contrast to bicalutamide and other pure antiandrogens or nsaas, antigonadotropic antiandrogens suppress gonadotropin secretion, which in turn diminishes testosterone production by the testes as well as the maintenance of the testes by fsh, resulting in atrophy and loss of their function. as such, bicalutamide and other nsaas may uniquely have the potential to preserve testicular function and spermatogenesis and thus male fertility relative to alternative therapies. in accordance with this notion, a study found that prolonged, high-dose bicalutamide treatment had minimal effects on fertility in male rats. however, another study found that low-dose bicalutamide administration resulted in testicular atrophy and reduced the germ cell count in the testes of male rats by almost 50%, though the rate of successful fertilization and pregnancy following mating was not assessed. additional studies found that bicalutamide decreased testes weights, altered testes histology, and decreased sperm count in male rats. yet another study found that bicalutamide has no effect on testes weights or spermatogenesis in male rats. treatment of men with exogenous testosterone or other aas results in suppression of gonadotropin secretion and gonadal testosterone production due to their antigonadotropic effects or activation of the ar in the pituitary gland, resulting in inhibition or abolition of spermatogenesis and fertility: treatment of an infertile man with testosterone does improve spermatogenesis, since exogenous administrated testosterone and its metabolite estrogen will suppress both gnrh production by the hypothalamus and luteinizing hormone production by the pituitary gland and subsequently suppress testicular testosterone production. also, high levels of testosterone are needed inside the testis and this can never be accomplished by oral or parenteral administration of androgens. suppression of testosterone production by the leydig cells will result in a deficient spermatogenesis, as can be seen in men taking anabolic–androgenic steroids. in contrast, pure ar antagonists would, in theory, result in the opposite (although reduced semen volume and sexual dysfunction may occur): it is theoretically a sound hypothesis that the spermatogenesis can be increased by indirectly stimulating fsh and lh secretions from the pituitary gland. however, for this to fructify, it requires the use of testosterone antagonist to nullify the negative feedback effect of circulating testosterone on the release of fsh and lh, thus augmenting the secretion of testosterone and spermatogenesis. unfortunately, a testosterone antagonist will be unacceptable to males, as it may reduce secondary sexual functions including erection and ejaculation that is vital for the successful fertilization. however, while bicalutamide does not appear to adversely influence testicular spermatogenesis, and healthy sperm can be produced within the testes during bicalutamide monotherapy, ar antagonists may be able to interfere with male fertility via interference with androgen signaling beyond the testes. the maturation as well as transport of sperm occurs not only in the testes but also outside of the testes in the epididymides and vas deferens, and these processes in these tissues are dependent on ar signaling similarly to testicular spermatogenesis. however, whereas androgen levels are extremely high in the testes, this is not true in the epididymides and vas deferens. as androgen levels are relatively low in these tissues, at least compared to the testes, bicalutamide may be able to block ar signaling in these parts of the body to an extent that is sufficient to interfere with male fertility. indeed, the aas mesterolone has been used to improve sperm quality and fertility in men because, apparently unlike other aas, it shows minimal antigonadotropic effects at typical clinical dosages but activates the ar and thereby supports sperm maturation in the epididymides. however, this use of mesterolone is controversial and its efficacy for such purposes is not fully certain. although bicalutamide alone would appear to have minimal detrimental effect on testicular spermatogenesis and hence on certain aspects of male fertility, other hormonal agents that bicalutamide may be combined with, including gnrh analogues and particularly estrogens (as in transgender hormone therapy), can have a considerable detrimental effect on fertility. this is largely a consequence of their antigonadotropic activity. antigonadotropic agents like high-dose cpa, high-dose androgens (e.g., testosterone esters), and gnrh antagonists (though notably not gnrh agonists in the case of fertility) produce hypogonadism and high rates of severe or complete infertility (e.g., severe oligospermia or complete azoospermia) in men. however, these effects are fully and often rapidly reversible with their discontinuation, even after prolonged treatment. in contrast, while estrogens at sufficiently high dosages similarly are able to produce hypogonadism and to abolish or severely impair spermatogenesis, this is not necessarily reversible in the case of estrogens and can be long-lasting after prolonged exposure. the difference is attributed to an apparently unique, direct cytotoxic and adverse effect of high concentrations of estrogens on the leydig cells of the testes. cytochrome p450 modulation it has been reported that bicalutamide may have the potential to inhibit the enzymes cyp3a4 and, to a lesser extent, cyp2c9, cyp2c19, and cyp2d6, based on in vitro research. however, no relevant inhibition of cyp3a4 has been observed in vivo with bicalutamide at a dose of 150 mg (using midazolam as a specific marker of cyp3a4 activity). in animals, bicalutamide has been found to be an inducer of certain cytochrome p450 enzymes. however, dosages of 150 mg/day or less have shown no evidence of this in humans. bicalutamide has been identified as a strong cyp27a1 (cholesterol 27-hydroxylase) inhibitor in vitro. cyp27a1 converts cholesterol into 27-hydroxycholesterol, an oxysterol that has multiple biological functions including direct, tissue-specific activation of the er (it has been characterized as a selective estrogen receptor modulator) and the liver x receptor. 27-hydroxycholesterol has been found to increase er-positive breast cancer cell growth via its estrogenic action, and hence, it has been proposed that bicalutamide and other cyp27a1 inhibitors may be effective as adjuvant therapies to aromatase inhibitors in the treatment of er-positive breast cancer. in addition to cyp27a1, bicalutamide has been found to bind to and inhibit cyp46a1 (cholesterol 24-hydroxylase) in vitro, but this has yet to be assessed and confirmed in vivo. p-glycoprotein inhibition bicalutamide, as well as enzalutamide, have been found to act as inhibitors of p-glycoprotein efflux and atpase activity. this action may reverse docetaxel resistance in prostate cancer cells by reducing transport of the drug out of these cells. gabaa receptor positive modulation all of the nsaas approved for the treatment of prostate cancer have been found to possess an off-target action of acting as weak non-competitive inhibitors of human gabaa receptor currents in vitro to varying extents. the ic50 values are 44 μm for flutamide (as hydroxyflutamide), 21 μm for nilutamide, 5.2 μm for bicalutamide, and 3.6 μm for enzalutamide. in addition, flutamide, nilutamide, and enzalutamide have been found to cause convulsions and/or death in mice at sufficiently high doses. bicalutamide was notably not found to do this, but this was likely simply due to the limited central nervous system penetration of bicalutamide in this species. in any case, enzalutamide is the only approved nsaa that has been found to be associated with a significantly increased incidence of seizures and other associated side effects clinically, so the relevance of the aforementioned findings with regard to bicalutamide and the other nsaas is unclear. miscellaneous bicalutamide has been identified as a potent antagonist of the protease-activated receptor 2 (par-2) and as a ligand and inhibitor of α2-macroglobulin. pharmacokinetics bicalutamide levels 50 mg/day150 mg/day cmax0.77 μg/ml(1.8 μmol/l)1.4 μg/ml(3.3 μmol/l) tmax31 hours39 hours css8.85 μg/ml(20.6 μmol/l)21.6–28.5 μg/ml(50.2–66.3 μmol/l) tss4–12 weeks4–12 weeks notes: all values are for (r)-bicalutamide. sources: the pharmacokinetics of bicalutamide are unaffected by food, age, body weight, renal impairment, and mild-to-moderate hepatic impairment. however, it has been observed that steady-state concentrations of bicalutamide are higher in japanese individuals than in caucasians, indicating that ethnicity may be associated with differences in the pharmacokinetics of bicalutamide in some instances. absorption bicalutamide is extensively and well-absorbed following oral administration, and its absorption is not affected by food. the absolute bioavailability of bicalutamide in humans is unknown due to its very low water solubility and hence lack of an assessable intravenous formulation. however, the absolute bioavailability of bicalutamide has been found to be high in animals at low doses (109% in mice at 10 mg/kg; 72% in rats at 1 mg/kg; 100% in dogs at 0.1 mg/kg), but diminishes with increasing doses such that the bioavailability of bicalutamide is low at high doses (10% in rats at 250 mg/kg; 31% in dogs at 100 mg/kg). in accordance, absorption of (r)-bicalutamide in humans is slow and extensive but saturable, with steady-state levels increasing linearly at a dosage of up to 150 mg/day and non-linearly at higher dosages. at higher dosages of 100 to 200 mg/day, absorption of bicalutamide is approximately linear, with a small but increasing departure from linearity above 150 mg/day. in terms of geometric mean steady-state concentrations of (r)-bicalutamide, the departures from linearity were 4%, 13%, 17%, and 32% with dosages of 100, 150, 200, and 300 mg/day, respectively. there is a plateau in steady-state levels of (r)-bicalutamide with bicalutamide dosages above 300 mg/day, and, accordingly, dosages of bicalutamide of 300 to 600 mg/day result in similar circulating concentrations of (r)-bicalutamide and similar degrees clinically of efficacy, tolerability, and toxicity. relative to 150 mg/day bicalutamide, levels of (r)-bicalutamide are about 15% higher at a dosage of 200 mg/day and about 50% higher at a dosage of 300 mg/day. in contrast to (r)-bicalutamide, the inactive enantiomer (s)-bicalutamide is much more rapidly absorbed (as well as cleared from circulation). steady-state concentrations of the drug are reached after 4 to 12 weeks of administration independently of dosage, with an approximate 10- to 20-fold progressive accumulation of circulating levels of (r)-bicalutamide. the relatively long time to reach steady-state is a product of the long elimination half-life of bicalutamide. with single 50 mg and 150 mg doses of bicalutamide, mean peak concentrations (cmax) of (r)-bicalutamide are 0.77 μg/ml (1.8 μmol/l) (at 31 hours) and 1.4 μg/ml (3.3 μmol/l) (at 39 hours), respectively. at steady-state, mean circulating concentrations (css) of (r)-bicalutamide with 50 mg/day and 150 mg/day bicalutamide are 8.85 μg/ml (20.6 μmol/l) and 21.6 μg/ml (50.2 μmol/l), respectively. in another 150 mg/day bicalutamide study, mean circulating concentrations of (r)-bicalutamide were 19.4 μg/ml (45.1 μmol/l) and 28.5 μg/ml (66.3 μmol/l) on days 28 and 84 (weeks 4 and 12) of treatment, respectively. there is wide interindividual variability, up to 15.7-fold, in steady-state (r)-bicalutamide levels with bicalutamide therapy. this is the case for all dosage levels of bicalutamide, and ranges in (r)-bicalutamide levels for different dosages show significant overlap. distribution the apparent oral volume of distribution (vss/f) at steady state of (r)-bicalutamide with oral administration of a single 5 to 80 mg dose of (r)-bicalutamide in a novel solid dispersion with a polymeric matrix of hydroxypropyl methylcellulose phthalate (hp55s) (also known as (r)-bicalutamide/hp55s) ranges from 22.53 ± 3.71 l to 25.38 ± 2.69 l. bicalutamide is highly protein-bound (96.1% for racemic bicalutamide, 99.6% for (r)-bicalutamide), mainly to albumin. it has negligible affinity for shbg and no affinity for corticosteroid-binding globulin. the tissue distribution of bicalutamide is not well-characterized. however, it has been reported that distribution studies with bicalutamide have shown that preferential (i.e., tissue-selective) accumulation in anabolic (e.g., muscle) tissues does not occur. there are no available data on hepatic bicalutamide concentrations in humans, but a rat study found that oral bicalutamide treatment resulted in 4-fold higher concentrations of the drug in the liver relative to plasma (a common finding with orally administered drugs, due to transfer through the hepatic portal system prior to reaching circulation). in men receiving 150 mg/day bicalutamide, concentrations of (r)-bicalutamide in semen were 4.9 μg/ml (11 μmol/l), and the amount of the drug that could potentially be delivered to a female partner during sexual intercourse is regarded as low (estimated at 0.3 μg/kg) and below the amount that is required to induce changes in the offspring