Pharmacology Bicalutamide

1 pharmacology

1.1 pharmacodynamics

1.1.1 antiandrogenic activity
1.1.2 other activities


1.2 pharmacokinetics

pharmacology

pharmacodynamics
antiandrogenic activity

bicalutamide acts highly selective competitive silent antagonist of ar (ic50 = 159–243 nm), major biological target of androgen sex hormones testosterone , dht, , hence antiandrogen. activity of bicalutamide lies in (r)-isomer. due selectivity ar, bicalutamide not bind other steroid hormone receptors , hence has no off-target hormonal activity (e.g., progestogenic, glucocorticoid, antimineralocorticoid). not inhibit 5α-reductase nor known inhibit other enzymes involved in androgen steroidogenesis (e.g., cyp17a1). although not bind estrogen receptors (ers), bicalutamide can increase estrogen levels secondary ar blockade when used monotherapy in males, , hence can have indirect estrogenic effects in males. bicalutamide neither suppresses nor inhibits androgen production in body (i.e., not act antigonadotropin or androgen steroidogenesis inhibitor or lower androgen levels) , hence exclusively mediates antiandrogenic effects antagonizing ar. in addition classical nuclear ar, bicalutamide has been assessed @ membrane androgen receptors (mars) , found act potent antagonist of zip9 (ic50 = 66.3 nm), whereas not appear interact gprc6a.

the affinity of bicalutamide ar relatively low approximately 50 100 times lower of dht, 2.5- 10-fold potent ar agonist testosterone in bioassays , main endogenous ligand of receptor in prostate gland. however, typical clinical dosages of bicalutamide result in circulating levels of drug thousands of times higher of testosterone , dht, allowing powerfully prevent them binding , activating receptor. true in case of surgical or medical castration, in testosterone levels in circulation approximately 95% reduced , dht levels in prostate gland 50 60% reduced. in women, levels of testosterone substantially lower in men (20- 40-fold), smaller doses of bicalutamide (e.g., 25 mg/day in hirsutism studies) necessary.

blockade of ar bicalutamide in pituitary gland , hypothalamus results in prevention of negative feedback of androgens on hypothalamic–pituitary–gonadal (hpg) axis in males , consequent disinhibition of pituitary luteinizing hormone (lh) secretion. this, in turn, results in increase in circulating lh levels , activation of gonadal production of testosterone , extension production of estradiol. levels of testosterone have been found increase 1.5- 2-fold (59–97% increase) , levels of estradiol 1.5- 2.5-fold (65–146% increase) in men treated 150 mg/day bicalutamide monotherapy. in addition testosterone , estradiol, there smaller increases in concentrations of dht, sex hormone-binding globulin, , prolactin. estradiol levels bicalutamide monotherapy similar in low-normal premenopausal female range while testosterone levels remain in high end of normal male range. testosterone concentrations not typically exceed normal male range due negative feedback on hpg axis increased concentrations of estradiol. bicalutamide influences hpg axis , increases hormone levels in men , not in women. due lower levels of androgens in women , lack of basal suppression of hpg axis in sex. evidenced effectiveness in treatment of prostate cancer , other androgen-dependent conditions, antiandrogenic actions of bicalutamide exceed impact of increased levels of testosterone results in. however, elevated levels of estradiol remain unopposed bicalutamide , responsible gynecomastia , feminizing side effects causes in men.

nsaa monotherapy, including bicalutamide, shows number of tolerability differences methods of androgen deprivation therapy incorporate surgical or medical castration. example, rates of hot flashes, depression, fatigue, , sexual dysfunction higher gnrh analogues nsaa monotherapy. thought because gnrh analogues suppress estrogen production in addition androgen production, resulting in estrogen deficiency. in contrast, nsaa monotherapy not decrease estrogen levels , in fact increases them, resulting in excess of estrogens compensates androgen deficiency , allows preservation of mood, energy, , sexual function. neurosteroids produced testosterone 3α-androstanediol , 3β-androstanediol, erβ agonists , former potent gabaa receptor positive allosteric modulator, may involved. in specific case of sexual dysfunction, additional possibility difference without concomitant suppression of androgen production, blockade of ar bicalutamide in brain incomplete , insufficient markedly influence sexual function.

under normal circumstances, bicalutamide has no capacity activate ar. however, in prostate cancer, mutations , overexpression of ar can accumulate in prostate gland cells can convert bicalutamide antagonist of ar agonist. can result in paradoxical stimulation of prostate cancer growth bicalutamide , responsible phenomenon of antiandrogen withdrawal syndrome, antiandrogen discontinuation paradoxically slows rate of prostate cancer growth.

in transgender women, breast development desired effect of antiandrogen and/or estrogen treatment. breast development , gynecomastia induced bicalutamide in people biologically male thought mediated increased activation of er secondary blockade of ar (resulting in disinhibition of er in breast tissue) , increased levels of estradiol. in addition fat deposition, connective tissue growth, , ductal development, bicalutamide has been found produce moderate lobuloalveolar development of breasts. however, full lobuloalveolar maturation necessary lactation , breastfeeding not occur without progestogen treatment.

bicalutamide monotherapy seems have minimal effect on spermatogenesis, testicular ultrastructure, , male fertility. seems because testosterone levels in testes (where ~95% of testosterone in males produced) extremely high (up 200-fold higher circulating levels) , small fraction (less 10%) of normal levels of testosterone in testes necessary maintain spermatogenesis. result, bicalutamide seems not able compete testosterone in sole part of body extent sufficient considerably interfere androgen signaling , function. however, suppression of gonadal androgen production, such taking estrogen, progestogen, or gnrh analogue bicalutamide, can compromise due own adverse effects on spermatogenesis , fertility.

other activities

bicalutamide has been found act inhibitor or inducer of cytochrome p450 enzymes including cyp3a4, cyp2c9, cyp2c19, , cyp2d6 in preclinical research, no evidence of has been found in humans treated 150 mg/day. has been identified in vitro strong inhibitor of cyp27a1 (cholesterol 27-hydroxylase) , inhibitor of cyp46a1 (cholesterol 24-hydroxylase), has yet assessed or confirmed in vivo or in humans , clinical significance remains unknown. bicalutamide has been found p-glycoprotein (abcb1) inhibitor. other first-generation nsaas , enzalutamide, has been found act weak non-competitive inhibitor of gabaa receptor-mediated currents in vitro (ic50 = 5.2 μm). however, unlike enzalutamide, bicalutamide has not been found associated seizures or other related adverse central effects, clinical relevance of finding uncertain.

pharmacokinetics

though absolute bioavailability in humans unknown, bicalutamide known extensively , well-absorbed. absorption not affected food. absorption of bicalutamide linear @ doses 150 mg/day , saturable @ doses above this, no further increases in steady-state levels of bicalutamide occurring @ doses above 300 mg/day. whereas absorption of (r)-bicalutamide slow, levels peaking @ 31 39 hours after dose, (s)-bicalutamide more rapidly absorbed. steady-state concentrations of drug reached after 4 12 months of treatment independently of dosage, 10- 20-fold progressive accumulation in levels of (r)-bicalutamide. long time steady-state levels result of bicalutamide s long elimination half-life. although takes long time bicalutamide reach steady-state concentrations, appears have antiandrogenic efficacy equivalent of flutamide (which has shorter elimination half-life , reaches steady-state levels faster) end of first day of treatment.

the tissue distribution of bicalutamide not well-characterized. amount of bicalutamide in semen potentially transferred female partner during sexual intercourse low , not thought important. based on animal studies rats , dogs thought bicalutamide not cross blood–brain barrier , hence not enter brain. such, thought peripherally selective antiandrogen. however, subsequent clinical studies found not case humans, indicating species differences; bicalutamide crosses human brain and, in accordance, produces effects , side effects consistent central antiandrogenic action. bicalutamide highly plasma protein bound (96.1% racemic bicalutamide, 99.6% (r)-bicalutamide) , bound albumin, negliglble binding shbg , corticosteroid-binding globulin.

bicalutamide metabolized in liver. (r)-bicalutamide metabolized , exclusively via hydroxylation cyp3a4 (r)-hydroxybicalutamide. metabolite glucuronidated ugt1a9. in contrast (r)-bicalutamide, (s)-bicalutamide metabolized rapidly , glucuronidation (without hydroxylation). none of metabolites of bicalutamide known active , levels of metabolites low in plasma, unchanged biclautamide predominates. due stereoselective metabolism of bicalutamide, (r)-bicalutamide has far longer terminal half-life (s)-bicalutamide , levels 10- 20-fold higher in comparison following single dose , 100-fold higher @ steady-state. (r)-bicalutamide has relatively long elimination half-life of 5.8 days single dose , 7 10 days following repeated administration.

bicalutamide eliminated in similar proportions in feces (43%) , urine (34%), while metabolites eliminated equally in urine , bile. bicalutamide excreted substantial extent in unmetabolized form, , both bicalutamide , metabolites eliminated glucuronide conjugates. glucuronide conjugates of bicalutamide , metabolites eliminated circulation rapidly, unlike unconjugated bicalutamide.

the pharmacokinetics of bicalutamide not affected consumption of food, person s age or body weight, renal impairment, or mild-to-moderate hepatic impairment. however, steady-state levels of bicalutamide higher in japanese individuals in white people.