However, while bicalutamide does not seem to be able to adversely influence testicular spermatogenesis, it may interfere with AR-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 bicalutamide with other medications, such as estrogens, progestogens, and GnRH 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
Bicalutamide 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. Bicalutamide has been found to be a P-glycoprotein (ABCB1) inhibitor. Like other first-generation NSAAs and enzalutamide, it has been found to act as a weak non-competitive inhibitor of GABAA receptor-mediated currents in vitro (IC50 = 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. Pharmacokinetics
Though its absolute bioavailability in humans is unknown, bicalutamide is known to be extensively and well-absorbed. Its absorption is not affected by food. The absorption of bicalutamide 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 bicalutamide 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 bicalutamides very long elimination half-life.The tissue distribution of bicalutamide is not well-characterized. 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. Based on animal studies with rats and dogs it was thought that bicalutamide could not cross the blood–brain barrier and hence could not enter the brain. As such, it was initially thought to be a peripherally selective antiandrogen.