|Systematic (IUPAC) name|
|Licence data||US FDA:|
|Protein binding||84 to 99%|
|Excretion||Biliary and renal|
|CAS Registry Number|
|ATC code||J02 D01 G01|
|PDB ligand ID||KTN (, )|
|Molecular mass||531.431 g/mol|
Ketoconazole () (synthetic imidazole antifungal drug used primarily to treat fungal infections. Ketoconazole is sold commercially as a tablet for oral administration (although this use has been discontinued in a number of countries), and in a variety of formulations for topical administration, such as creams (used to treat tinea; cutaneous candidiasis, including candidal paronychia; and pityriasis versicolor) and shampoos (used primarily to treat dandruff—seborrhoeic dermatitis of the scalp).
The less toxic and generally more effective triazole antifungal agents fluconazole and itraconazole are usually preferred for systemic use. In 2013 the European Medicines Agency's 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. The oral formulation of ketoconazole was discontinued in Australia in 2013 and in China in 2015.
Medical uses 1
- Topical antifungal 1.1.1
- Systemic antifungal 1.1.2
- Antiandrogenic and antiglucocorticoid 1.2
- Veterinary 1.3
- Antifungal 1.1
- Mechanism of action 2
- Administration and absorption 3
- Resistance 4
Off-label uses 5
- Hair loss 5.1
- Adverse effects 6
- History 7
- See also 8
- References 9
- Further reading 10
- External links 11
Topically administered ketoconazole is usually prescribed for fungal infections of the skin and mucous membranes, such as athlete's foot, ringworm, candidiasis (yeast infection or thrush), jock itch, and tinea versicolor. Topical ketoconazole is also used as a treatment for dandruff (seborrheic dermatitis of the scalp) and for seborrheic dermatitis on other areas of the body, perhaps acting in these conditions by suppressing levels of the fungus Malassezia furfur on the skin.
Ketoconazole has activity against many kinds of fungi that may cause human disease, such as Candida, Histoplasma, Coccidioides, and Blastomyces (although it is not active against Aspergillus). First synthesized in 1977, ketoconazole was the first orally-active azole antifungal medication. However, ketoconazole has largely been replaced as a first-line systemic antifungal medication by other azole antifungal agents, such as itraconazole, because of ketoconazole's greater toxicity, poorer absorption, and more limited spectrum of activity.
Ketoconazole is used orally in dosages of 200 to 400 mg per day in the treatment of superficial and deep fungal infections.
Antiandrogenic and antiglucocorticoid
The side effects of ketoconazole are sometimes harnessed in the treatment of non-fungal conditions. While ketoconazole blocks the synthesis of the sterol ergosterol in fungi, in human beings, at high dosages (>800 mg/day), it potently inhibits the activity of several enzymes necessary for the conversion of cholesterol to steroid hormones such as testosterone and cortisol. Specifically, ketoconazole has been shown to inhibit cholesterol side-chain cleavage enzyme, which converts cholesterol to pregnenolone, 17α-hydroxylase and 17,20-lyase, which convert pregnenolone into androgens, and 11β-hydoxylase, which converts 11-deoxycortisol to cortisol. All of these enzymes are mitochondrial cytochrome p450 enzymes. Based on these antiandrogen and antiglucocorticoid effects, ketoconazole has been used with some success as a second-line treatment for certain forms of advanced prostate cancer and for the suppression of glucocorticoid synthesis in the treatment of Cushing's syndrome. However, in the treatment of prostate cancer, concomitant glucocorticoid administration is needed to prevent adrenal insufficiency. Ketoconazole has additionally been used, in lower dosages, to treat hirsutism and, in combination with a GnRH analogue, male-limited precocious puberty. In any case, the risk of hepatotoxicity with ketoconazole limits its use in all of these indications, especially in those that are benign such as hirsutism.
This medication is also sometimes prescribed by veterinarians for use on pets, often as unflavored tablets that may need to be cut to smaller size for correct dosage.
Mechanism of action
As an antifungal, ketoconazole 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, ketoconazole works principally by inhibiting the enzyme cytochrome P450 14α-demethylase (P45014DM). 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 ketoconazole, as they have been found to have a greater affinity for fungal cell membranes.
As an antiandrogen, ketoconazole operates through at least two mechanisms of action. First, and most notably, high oral doses of ketoconazole (e.g. 400 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.
Administration and absorption
When administered orally, ketoconazole 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. Ketoconazole is very lipophilic and tends to accumulate in fatty tissues.
Resistance to ketoconazole 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.
Ketoconazole shampoo in conjunction with an oral 5α-reductase inhibitor has been used off label to treat androgenic alopecia. The antifungal properties of ketoconazole reduce scalp microflora and consequently may reduce follicular inflammation that contributes to alopecia.
Limited clinical studies suggest ketoconazole shampoo used either alone or in combination with other treatments may be useful in reducing hair loss.
It is a pregnancy category C drug because animal testing has shown it to cause teratogenesis when administered in high doses. Recently, the administration of systemic ketoconazole to two pregnant women for treatment of Cushing's syndrome was reported to have no adverse effects, but this small sample precludes drawing any meaningful conclusions. A subsequent trial in Europe failed to show a risk to infants of mothers receiving ketoconazole.
On July 2013, the U.S. Food and Drug Administration (FDA) issued a warning that taking ketoconazole orally can cause severe liver injuries and adrenal gland problems. It recommends Nizoral oral tablets should not be a first-line treatment for any fungal infection. Nizoral should be used for the treatment of certain fungal infections, known as endemic mycoses, only when alternative antifungal therapies are not available or tolerated.
The topical formulations of Nizoral have not been associated with liver damage, adrenal problems, or drug interactions. These formulations include creams, shampoos, foams, and gels applied to the skin, unlike the Nizoral tablets, which are taken by mouth.
Ketoconazole was discovered in 1976 at Janssen Pharmaceuticals.
- Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust.
- "European Medicines Agency recommends suspension of marketing authorisations for oral ketoconazole". Press Release. European Medicines Agency. 2013-07-26.
- TGA. 10 October 2013 Oral ketoconazole (Nizoral) 200 mg tablets: Product deregistration
- "国家食品药品监督管理总局关于停止生产销售使用酮康唑口服制剂的公告（2015年第85号）" (in 中文).
- Phillips RM, Rosen T (2013). "Topical Antifungal Agents". In Wolverton SE. Comprehensive Dermatologic Therapy (3rd ed.). Philadelphia: Saunders. pp. 460–472.
- Neider R, Fritsch PO (2012). "Other Eczematous Eruptions". In Bolognia JL. Dermatology (3rd ed.). Philadelphia: Saunders. pp. 219–221.
- Young BK, Brodell RT, Cooper KD (2013). "Therapeutic Shampoos". In Wolverton SE. Comprehensive Dermatologic Therapy (3rd ed.). Philadelphia: Saunders. pp. 562–569.
- Finkel R, Cubeddu LX, Clark MA (2009). Pharmacology (4th ed.). Baltimore: Lippincott Williams & Wilkins. p. 411.
- Kauffman CA (2004). "Introduction to the Mycoses". In Goldman L, Ausiello, D. Cecil Textbook of Medicine (22nd ed.). Philadelphia: Saunders. p. 2043.
- Kenneth L. Becker (2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 1197–.
- "MedScape". Ectopic Cortisol Production Derived From Malignant Testicular Masses: Treatment and Management. Nature Publishing Group. Retrieved 18 April 2015.
- Loose, D (May 1983). "Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes.". JCI 71 (5): 1495–1499.
- Zelefsky MJ, Eastham JA, Sartor OA, Kantoff P (2008). DeVita VT, Lawrence TS, Rosenberg SA, ed. Cancer: Principles & Practice of Oncology (8th ed.). Philadelphia: Lippincott Williams & Wilkins. p. 1443.
- Loli P, Berselli ME, Tagliaferri M (December 1986). "Use of ketoconazole in the treatment of Cushing's syndrome". J. Clin. Endocrinol. Metab. 63 (6): 1365–71.
- KuKanich B (January 2008). "A review of selected systemic antifungal drugs for use in dogs and cats". Veterinary Medicine.
- Loose DS, Kan PB, Hirst MA, Marcus RA, Feldman D (May 1983). "Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes". J. Clin. Invest. 71 (5): 1495–9.
- Witjes FJ, Debruyne FM, Fernandez del Moral P, Geboers AD (May 1989). "Ketoconazole high dose in management of hormonally pretreated patients with progressive metastatic prostate cancer. Dutch South-Eastern Urological Cooperative Group". Urology 33 (5): 411–5.
- De Coster R, Wouters W, Bruynseels J (January 1996). "P450-dependent enzymes as targets for prostate cancer therapy". J. Steroid Biochem. Mol. Biol. 56 (1–6 Spec No): 133–43.
- Eil C (August 1992). "Ketoconazole binds to the human androgen receptor". Horm. Metab. Res. 24 (8): 367–70.
- Loose DS, Stover EP, Feldman D (1983). "Ketoconazole binds to glucocorticoid receptors and exhibits glucocorticoid antagonist activity in cultured cells". J. Clin. Invest. 72 (1): 404–8.
- Duret C, Daujat-Chavanieu M, Pascussi JM, Pichard-Garcia L, Balaguer P, Fabre JM, Vilarem MJ, Maurel P, Gerbal-Chaloin S (2006). "Ketoconazole and miconazole are antagonists of the human glucocorticoid receptor: consequences on the expression and function of the constitutive androstane receptor and the pregnane X receptor". Mol. Pharmacol. 70 (1): 329–39.
- Chin TW, Loeb M, Fong IW (August 1995). "Effects of an acidic beverage (Glass of Orange Juice) on absorption of ketoconazole". Antimicrobial Agents and Chemotherapy 39 (8): 1671–5.
- Cartledge, JD; Midgley, J; Gazzard, BG (1997). "Clinically significant azole cross-resistance in Candida isolates from HIV-positive patients with oral candidosis.". AIDS 11 (15): 1839–44.
- Sanglard, D; Ischer, F; Monod, M; Bille, J (1997). "Cloning of Candida albicans genes conferring resistance to azole antifungal agents: characterization of CDR2, a new multidrug ABC transporter gene.". Microbiology 143 (Pt 2): 405–16.
- McElwee KJ, Shapiro JS (June 2012). "Promising therapies for treating and/or preventing androgenic alopecia". Skin Therapy Lett. 17 (6): 1–4.
- Piérard-Franchimont C, De Doncker P, Cauwenbergh G, Piérard GE (1998). "Ketoconazole shampoo: effect of long-term use in androgenic alopecia". Dermatology (Basel) 196 (4): 474–7.
- Piérard-Franchimont C, Goffin V, Henry F, Uhoda I, Braham C, Piérard GE (October 2002). "Nudging hair shedding by antidandruff shampoos. A comparison of 1% ketoconazole, 1% piroctone olamine and 1% zinc pyrithione formulations". Int J Cosmet Sci 24 (5): 249–56.
- Khandpur S, Suman M, Reddy BS (August 2002). "Comparative efficacy of various treatment regimens for androgenetic alopecia in men". J. Dermatol. 29 (8): 489–98.
- Amado JA, Pesquera C, Gonzalez EM, Otero M, Freijanes J, Alvarez A (March 1990). "Successful treatment with ketoconazole of Cushing's syndrome in pregnancy". Postgrad Med J 66 (773): 221–3.
- Berwaerts J, Verhelst J, Mahler C, Abs R (June 1999). "Cushing's syndrome in pregnancy treated by ketoconazole: case report and review of the literature". Gynecol. Endocrinol. 13 (3): 175–82.
- Kazy Z, Puhó E, Czeizel AE (March 2005). "Population-based case-control study of oral ketoconazole treatment for birth outcomes". Congenit Anom (Kyoto) 45 (1): 5–8.
- "FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems". FDA Drug Safety Communication (
- Heeres J, Backx LJ, Mostmans JH, Van Cutsem J (August 1979). "Antimycotic imidazoles. part 4. Synthesis and antifungal activity of ketoconazole, a new potent orally active broad-spectrum antifungal agent". J. Med. Chem. 22 (8): 1003–5.
- PubPK | Ketoconazole pharmacokinetics
- Eil C (Aug 1992). "Ketoconazole binds to the human androgen receptor". Horm Metab Res 24 (8): 367–370.
- Janssen Pharmaceutica | Fungal infections