Pharmacodynamics Antifungal activity As an antifungal,<unk>  is structurally similar to imidazole, and interferes with the fungal synthesis of ergosterol, a constituent of fungal cell membranes, as well as certain enzymes. As with all azole antifungal agents,<unk>  works principally by inhibiting the enzyme cytochrome P450 14α-demethylase (CYP51A1). This enzyme participates in the sterol biosynthesis pathway that leads from lanosterol to ergosterol. Lower doses of fluconazole and itraconazole are required to kill fungi compared to<unk> , as they have been found to have a greater affinity for fungal cell membranes. Resistance to<unk>  has been observed in a number of clinical fungal isolates, including Candida albicans. Experimentally, resistance usually arises as a result of mutations in the sterol biosynthesis pathway. Defects in the sterol 5-6 desaturase enzyme reduce the toxic effects of azole inhibition of the 14-alpha demethylation step. Multidrug-resistance (MDR) genes can also play a role in reducing cellular levels of the drug. As azole antifungals all act at the same point in the sterol pathway, resistant isolates are normally cross-resistant to all members of the azole family. Antihormonal activity As an antiandrogen,<unk>  operates through at least two mechanisms of action. First, and most notably, high oral doses of<unk>  (e.g. 40 mg three times per day) block both testicular and adrenal androgen biosynthesis, leading to a reduction in circulating testosterone levels. It produces this effect through inhibition of 17α-hydroxylase and 17,20-lyase, which are involved in the synthesis and degradation of steroids, including the precursors of testosterone. Due to its efficacy at reducing systemic androgen levels,<unk>  has been used with some success as a treatment for androgen-dependent prostate cancer. Second,<unk>  is an androgen receptor antagonist, competing with androgens such as testosterone and dihydrotestosterone (DHT) for binding to the androgen receptor. This effect is thought to be quite weak however, even with high oral doses of<unk> .<unk> , along with miconazole, has been found to act as an antagonist of the glucocorticoid receptor.<unk>  is a racemic mixture consisting of cis-(2S,4R)-(−) and cis-(2R,4S)-(+) enantiomers. The cis-(2S,4R) isomer was more potent in inhibiting progesterone 17α,20-lyase than its enantiomer (IC50 values of 0.05 and 2.38 μM, respectively) and in inhibiting 11β-hydroxylase (IC50 values of 0.152 and 0.608 μM, respectively). Both isomers were relatively weak inhibitors of human placental aromatase. Oral<unk>  has been used clinically as a steroidogenesis inhibitor in men, women, and children at dosages of 200 to 1,200 mg/day. Numerous small studies have investigated the effects of oral<unk>  on hormone levels in humans. It has been found in men to significantly decrease testosterone and estradiol levels and to significantly increase luteinizing hormone, progesterone, and 17α-hydroxyprogesterone levels, whereas levels of androstenedione, follicle-stimulating hormone, and prolactin were unaffected. The ratio of testosterone to estradiol is also decreased during oral<unk>  therapy in men. Suppression of testosterone levels by<unk>  is generally partial and has often been found to be transient. Better effects on suppression of testosterone levels have been observed in men when<unk>  is combined with a GnRH agonist to suppress the hypothalamic–pituitary–gonadal axis, which prevents compensatory upregulation of luteinizing hormone secretion and consequent activation of gonadal testosterone production. In premenopausal women with polycystic ovary syndrome,<unk>  has been found to significantly decrease levels of androstenedione and testosterone and significantly increase levels of 17α-hydroxyprogesterone and estradiol. Studies in postmenopausal women with breast cancer have found that<unk>  significantly decreases androstenedione levels, slightly decreases estradiol levels, and does not affect estrone levels. This indicates minimal inhibition of aromatase by<unk>  in vivo in humans.<unk>  has also been found to decrease levels of endogenous corticosteroids, such as cortisol, corticosterone, and aldosterone, as well as vitamin D.<unk>  has been found to displace dihydrotestosterone and estradiol from sex hormone-binding globulin in vitro, but this was not found to be relevant in vivo. Other activities<unk>  has been found to inhibit the activity of the cation channel TRPM5. Pharmacokinetics When administered orally,<unk>  is best absorbed at highly acidic levels, so antacids or other causes of decreased stomach acid levels will lower the drug's absorption. Absorption can be increased by taking it with an acidic beverage, such as cola.<unk>  is very lipophilic and tends to accumulate in fatty tissues.
Ketoconazole
Levoketoconazole
Itraconazole
Sertaconazole
Miconazole
Terbinafine
Efinaconazole
Posaconazole