cells which over-express the AR, enzalutamide induced apoptosis whereas bicalutamide did not. Furthermore, enzalutamide 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 enzalutamide in men with prostate cancer have been performed. Changes in hormone levels Enzalutamide 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 Enzalutamide has approximately 8-fold higher binding affinity for the androgen receptor (AR) compared to bicalutamide. One study found an of 21 nM for enzalutamide 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 enzalutamide 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 enzalutamide treatment in clinical trials. Resistance mechanisms in prostate cancer Enzalutamide 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 Enzalutamide 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 Enzalutamide 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 enzalutamide 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 enzalutamide in rats is 89.7%. Steady-state concentrations of enzalutamide are achieved within 28 days