Pharmacodynamics<unk>  acts as a selective silent antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). Unlike the first-generation NSAA bicalutamide,<unk>  does not promote translocation of AR to the cell nucleus and in addition prevents binding of AR to deoxyribonucleic acid (DNA) and AR to coactivator proteins. As such, it has been described as an AR signaling inhibitor in addition to antagonist. The drug is described as a "second-generation" NSAA because it has greatly increased efficacy as an antiandrogen relative to so-called "first-generation" NSAAs like flutamide and bicalutamide. The drug has only 2-fold lower affinity for the AR than DHT, the endogenous ligand of the AR in the prostate gland. When LNCaP cells (a prostate cancer cell line) engineered to express elevated levels of AR (as found in patients with advanced prostate cancer) were treated with<unk> , the expression of androgen-dependent genes PSA and TMPRSS2 was down regulated in contrast to bicalutamide where the expression was upregulated. In VCaP cells which over-express the AR,<unk>  induced apoptosis whereas bicalutamide did not. Furthermore,<unk>  behaves as an antagonist of the W741C mutant AR in contrast to bicalutamide which behaves as a pure agonist when bound to the W741C mutant. Dose-ranging studies of<unk>  in men with prostate cancer have been performed. Changes in hormone levels<unk>  monotherapy at a dosage of 160 mg/day has been found to increase circulating levels of testosterone by 114.3%, dihydrotestosterone (DHT) by 51.7%, estradiol by 71.7%, sex hormone-binding globulin (SHBG) by 100.6%, dehydroepiandrosterone (DHEA) by 9.6%, androstenedione by 51.1%, luteinizing hormone (LH) by 184.7%, follicle-stimulating hormone (FSH) by 47.0%, and prolactin by 16.8%. These changes in hormone levels are similar to those with high-dose bicalutamide monotherapy. The median maximum decrease in levels of prostate-specific antigen (PSA) levels was 99.6%. Comparison with other antiandrogens<unk>  has approximately 8-fold higher binding affinity for the androgen receptor (AR) compared to bicalutamide. One study found an of 21 nM for<unk>  and 160 nM for bicalutamide at the AR in the LNCaP cell line (7.6-fold difference), while another found respective IC50 values of 36 nM and 159 nM (4.4-fold difference). In accordance, clinical findings suggest that<unk>  is a significantly more potent and effective antiandrogen in comparison to first-generation NSAAs such as bicalutamide, flutamide, and nilutamide. Also, unlike with the first-generation NSAAs, there has been no evidence of hepatotoxicity or elevated liver enzymes in association with<unk>  treatment in clinical trials. Resistance mechanisms in prostate cancer<unk>  is only effective for a certain period of time, after that the growth of the cancer is not inhibited by this antiandrogen. The mechanisms of resistance to<unk>  are being intensively studied. Currently, several mechanisms have been found: * AR mutations * AR splice variants * Glucocorticoid receptor bypass * Increase in flux of glycolysis * Autophagy mediated resistance * Wnt signaling activation * Increase in intra-tumoral androgen biosynthesis mediated by AKR1C3 enzyme * Interleukin 6 signaling mediated resistance Cytochrome P450 modulation<unk>  is reported to be a strong inducer of the enzyme CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19, and can affect the circulating concentrations of drugs that are metabolized by these enzymes. Pharmacokinetics The bioavailability of<unk>  in humans is unknown, but is at least 84.6% based on the amount recovered from urine and bile in excretion studies. Similarly, the bioavailability of<unk>  in rats is 89.7%. Steady-state concentrations of<unk>  are achieved within 28 days of treatment initiation. The plasma protein binding of<unk>  is 97 to 98%, while that of N-desmethylenzalutamide (NDME), its major metabolite, is 95%.<unk>  is primarily bound to albumin. The medication is metabolized in the liver, mainly by the cytochrome P450 enzymes CYP2C8 and CYP3A4. CYP2C8 is primarily responsible for the formation of NDME.<unk>  has a long elimination half-life of 5.8 days on average, with a range of 2.8 to 10.2 days. The elimination half-life of NDME is even longer, at about 7.8 to 8.6 days.<unk>  is eliminated 71.0% in urine, 13.6% in bile, and 0.39% in feces.
Enzalutamide
Bicalutamide
Flutamide
Apalutamide
Nilutamide
Topilutamide
Darolutamide
Tamoxifen