of laboratory animals. based on animal research, it was initially thought that bicalutamide was unable to cross the blood–brain barrier into the central nervous system and hence would be a peripherally-selective antiandrogen in humans. this conclusion was drawn from the finding that bicalutamide does not increase lh or testosterone levels in multiple tested animal species (including rats and dogs). ar antagonists like flutamide normally do this by blocking ars in the pituitary gland and hypothalamus in the brain and thereby disinhibiting the hpg axis. in humans however, bicalutamide has been found to increase lh and testosterone levels, and to a comparable extent relative to flutamide and nilutamide. this occurs to a significant extent at even a very low dosage of 10 mg/day bicalutamide. as such, it appears that there are species differences in the central penetration of bicalutamide and that the medication does indeed cross the blood–brain barrier and affect central function in humans. this is supported by potential side effects of bicalutamide, in spite of increased testosterone levels, like hot flashes and decreased sexual interest in men. however, a clinical study comparing bicalutamide and flutamide in men found that bicalutamide had less influence on the hpg axis than flutamide, suggesting that bicalutamide might have a limited degree of peripheral selectivity, at least compared to other nsaas, in humans. bicalutamide has been identified as a substrate of p-glycoprotein and of the breast cancer resistance protein (bcrp), though not of the multidrug resistance-associated protein 1 (mrp1). this may be involved in tumor resistance to bicalutamide. p-glycoprotein is also known to play a major role in excluding drugs from the brain due to efflux back across the blood–brain barrier. metabolism the metabolism of bicalutamide is hepatic and stereoselective. the inactive (s)-enantiomer is metabolized mainly by glucuronidation and is rapidly cleared from circulation, while the active (r)-isomer is slowly hydroxylated and then glucuronidated. in accordance, the active (r)-enantiomer has a far longer elimination half-life than the (s)-isomer, and circulating levels of (r)-bicalutamide are 10- to 20-fold and 100-fold higher than those of (s)-bicalutamide after a single dose and at steady-state, respectively. (r)-bicalutamide is almost exclusively metabolized via hydroxylation into (r)-hydroxybicalutamide by the cytochrome p450 enzyme cyp3a4. bicalutamide is also glucuronidated by ugt1a9, a udp-glucuronyltransferase, into bicalutamide glucuronide, and (r)-hydroxybicalutamide glucuronide is formed from the metabolism of (r)-hydroxybicalutamide by ugt1a9. similar to the inactive (s)-enantiomer of bicalutamide, (r)-hydroxybicalutamide is glucuronidated and rapidly cleared from circulation. none of the metabolites of bicalutamide are known to be active. following administration of bicalutamide, only low concentrations of the metabolites are detectable in blood plasma, while unchanged bicalutamide predominates. (r)-bicalutamide has a long elimination half-life of 5.8 days with a single dose, and an elimination half-life of 7 to 10 days with repeated administration, which allows for convenient once-daily dosing of bicalutamide. bicalutamide metabolism in humans bicalutamide (s)-bicalutamide glucuronide (r)-hydroxybicalutamide (r)-hydroxybicalutamide glucuronide glucuronidation via ugt1a9 glucuronidation via ugt1a9 hydroxylation via cyp3a4 this diagram illustrates the primary metabolic pathways involved in the metabolism of bicalutamide in humans. elimination bicalutamide is eliminated in feces (43%) and urine (34%), whereas its metabolites are eliminated in approximately equal proportions in urine and bile. it is excreted to a substantial extent in its unmetabolized form, with both bicalutamide and its metabolites excreted mainly as glucuronide conjugates. graphs bicalutamide levels during therapy with bicalutamide (r)-bicalutamide levels after a single 5 to 80 mg dose of (r)-bicalutamide/hp55s in men. the mean elimination half-life of (r)-bicalutamide in this study was 5.6 to 7.5 days. bicalutamide levels after a single 50 mg dose of bicalutamide in men. the mean elimination half-life of bicalutamide in this study was 4.2 days. bicalutamide levels after a single 10, 30, or 50 mg dose of bicalutamide in men. the mean elimination half-life of bicalutamide in this study was 5.5 to 6.3 days. mean plasma (r)-bicalutamide concentrations with 10 to 600 mg/day bicalutamide in men over the course of 12 weeks. steady-state plasma levels of (r)-bicalutamide as a function of bicalutamide dosage (10 to 600 mg/day) in men. note the divergence from linearity at dosages above 200 mg/day, which demonstrates the saturation of absorption with higher dosages of bicalutamide.