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, ketoconazole operates through at least two mechanisms of action. First, and most notably, high oral doses of ketoconazole (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, ketoconazole has been used with some success as a treatment for androgen-dependent prostate cancer. Second, ketoconazole 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 ketoconazole.Ketoconazole, along with miconazole, has been found to act as an antagonist of the glucocorticoid receptor.Ketoconazole 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 ketoconazole has been used clinically as a steroidogenesis inhibitor in men, women, and children at dosages of 200 to 1,200 mg/day.
Oral ketoconazole is now only indicated for use in these countries when the indication is a severe or life-threatening systemic infection and alternatives are unavailable. However, topical ketoconazole, which does not distribute systemically, is safe and widely used still.Ketoconazole HRA was approved for use in the European Union for treatment of Cushings syndrome in November 2013.As of March 2019, oral levoketoconazole (developmental code name COR-003, tentative brand name Recorlev) is phase III clinical trials for the treatment of Cushings syndrome. Oral levoketoconazole may have a lower risk of liver toxicity than oral ketoconazole. Society and culture
Generic names
Ketoconazole is the generic name of the drug and its INN, USAN, BAN, and JAN. Brand names
Ketoconazole has been marketed under a large number of brand names. Availability
Ketoconazole is available widely throughout the world.In 2013, the European Medicines Agencys Committee on Medicinal Products for Human Use (CHMP) recommended that a ban be imposed on the use of oral ketoconazole for systemic use in humans throughout the European Union, after concluding that the risk of serious liver injury from systemic ketoconazole outweighs its benefits. Veterinary use
Ketoconazole is sometimes prescribed as an antifungal by veterinarians for use in pets, often as unflavored tablets that may need to be cut to smaller size for correct dosage. References
External links
"Ketoconazole". Drug Information Portal. U.S. National Library of Medicine.