|Systematic (IUPAC) name|
|Licence data||US FDA:|
|Protein binding||84 to 99%|
|Excretion||Biliary and renal|
|ATC code||J02 D01 G01|
|PDB ligand ID||KTN (, )|
|Mol. mass||531.431 g/mol|
|(what is this?)|
Ketoconazole // is a synthetic, imidazole antifungal medication 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. The European Medicines Agency's Committee on Medicinal Products for Human Use (CHMP) has 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. In Australia, the oral formulation of ketoconazole has already been discontinued.
- 1 Medical uses
- 2 Mechanism of action
- 3 Administration and absorption
- 4 Resistance
- 5 Off-label uses
- 6 Adverse effects
- 7 Synthesis
- 8 History
- 9 References
- 10 Further reading
- 11 External links
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.
Antiandrogenic and antiglucocorticoid
The side effects of ketoconazole are sometimes harnessed in the treatment of nonfungal conditions. While ketoconazole blocks the synthesis of the plant sterol ergosterol in fungi, in human beings it inhibits the activity of several enzymes necessary for the conversion of cholesterol to steroid hormones such as testosterone and cortisol. Based on these antiandrogen and antiglucocorticoid effects, ketoconazole has been used 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.
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 14-alpha-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 cytochrome P450 isozyme 3A4 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 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 androgen receptor binding. This effect is thought to be quite weak, 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.
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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 systemic antiandrogens treatment has been used off label to treat androgenic alopecia. Its antifungal properties reduce scalp microflora and consequently may reduce follicular inflammation that contributes to alopecia. Furthermore, it blocks the local synthesis of dihydrotestosterone in the scalp, as well as acts as an antagonist of the androgen receptor. Hence, ketoconazole when used with systemic antiandrogens may result in a more complete blockade of androgen receptors in the scalp and consequently may lead to a more effective treatment of androgenic alopecia.
|This section requires expansion. (May 2013)|
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.
The first racemic synthesis of ketoconazole was published in 1979. In this synthesis, cis- and trans-isomers were separated by crystallization because only the two cis-enantiomers are used in the commercially available drug.
The synthesis was started with dichloroacetophenone (1) and glycerine. The ketal was directly brominated to yield alcohol 2. This was further transformed into the corresponding benzoate ester 3 and at this stage cis- and trans-isomers were separated. The imidazole residue was then introduced followed by a basic hydrolysis of the ester moiety. The free hydroxyl group of 5 was converted into the mesylate and was then replaced by substituent 7 to yield ketoconazole 8 in six steps and an overall yield of 12%.
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- "European Medicines Agency recommends suspension of marketing authorisations for oral ketoconazole". Press Release. European Medicines Agency. 2013-07-26.
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- Ketoconazole | Patient information
- PubPK | Ketoconazole pharmacokinetics
- Eil C (Aug 1992). "Ketoconazole binds to the human androgen receptor". Horm Metab Res 24 (8): 367–370. doi:10.1055/s-2007-1003337. PMID 1526623.
- Janssen Pharmaceutica | Fungal infections