Ketoconazole

Source: Wikipedia, the free encyclopedia.

Ketoconazole
(2R,4S)-(+)-ketoconazole (top)
(2S,4R)-(−)-ketoconazole (bottom)
Ball-and-stick model of (2R,4S)-(+)-ketoconazole
Clinical data
Pronunciation/ˌkiːtoʊˈkoʊnəˌzoʊl, -zɒl/[1][2]
Trade namesNizoral, others
Other namesR-41400; KW-1414
AHFS/Drugs.comMonograph
MedlinePlusa682816
License data
Pregnancy
category
  • AU: B3
cream, shampoo, solution)
ATC code
Legal status
Legal status
Pharmacokinetic data
BioavailabilityBy mouth: 37–97%[8]
Protein binding84 to 99%
MetabolismExtensive liver (predominantly oxidation, O-dealkylation)
MetabolitesN-deacetyl ketoconazole
Elimination half-lifeBiphasic
ExcretionBile duct (major) and kidney[9]
Identifiers
  • 1-[4-[4-[[2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]ethanone
JSmol)
ChiralityRacemic mixture[9][10]
  • O=C(N5CCN(c4ccc(OC[C@@H]1O[C@](OC1)(c2ccc(Cl)cc2Cl)Cn3ccnc3)cc4)CC5)C
  • InChI=1S/C26H28Cl2N4O4/c1-19(33)31-10-12-32(13-11-31)21-3-5-22(6-4-21)34-15-23-16-35-26(36-23,17-30-9-8-29-18-30)24-7-2-20(27)14-25(24)28/h2-9,14,18,23H,10-13,15-17H2,1H3/t23-,26-/m0/s1 checkY
  • Key:XMAYWYJOQHXEEK-OZXSUGGESA-N checkY
 ☒NcheckY (what is this?)  (verify)
Stada
Nizoral

Ketoconazole, sold under the brand name Nizoral among others, is an

pityriasis versicolor, dandruff, and seborrheic dermatitis.[12] Taken by mouth it is a less preferred option and only recommended for severe infections when other agents cannot be used.[11] Other uses include treatment of excessive male-patterned hair growth in women and Cushing's syndrome.[11]

Common

adrenocortical insufficiency, and anaphylaxis.[11][13] It is an imidazole and works by hindering the production of ergosterol required for the fungal cell membrane, thereby slowing growth.[11]

Ketoconazole was patented in 1977 by Belgian pharmaceutical company

withdrawn in the European Union and in Australia in 2013,[17][18] and in China in 2015.[19] In addition, its use was restricted in the United States and Canada in 2013.[18]

Medical uses

Topical antifungal

Topically administered ketoconazole is usually prescribed for fungal infections of the skin and mucous membranes, such as

seborrheic dermatitis on other areas of the body, perhaps acting in these conditions by suppressing levels of the fungus Malassezia furfur on the skin.[20][21][22]

Systemic antifungal

Ketoconazole has activity against many kinds of fungi that may cause human disease, such as

azole antifungal agents, such as itraconazole, because of ketoconazole's greater toxicity, poorer absorption, and more limited spectrum of activity.[23][24]

Ketoconazole is used orally in dosages of 200 to 400 mg per day in the treatment of superficial and deep fungal infections.[25]

Off-label uses

Hair loss

Ketoconazole 2% gel

Ketoconazole shampoo in conjunction with an oral

androgenic alopecia. It was speculated that antifungal properties of ketoconazole reduce scalp microflora and consequently may reduce follicular inflammation that contributes to alopecia.[26]

Limited clinical studies suggest ketoconazole shampoo used either alone[27][28] or in combination with other treatments[29] may be useful in reducing hair loss in some cases.[30]

Hormonal

See also: Steroidogenesis inhibitor and CYP17A1 inhibitor

The side effects of ketoconazole are sometimes harnessed in the treatment of non-fungal conditions. While ketoconazole blocks the synthesis of the sterol

male-limited precocious puberty.[25] 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.[25]

Ketoconazole has been used to prevent the

GnRH agonist therapy in men with prostate cancer.[35]

Contraindications

Oral ketoconazole has various contraindications, such as concomitant use with certain other drugs due to known drug interactions.[6] Other contraindications of oral ketoconazole include liver disease, adrenal insufficiency, and known hypersensitivity to oral ketoconazole.[6]

Side effects

Gastrointestinal

Vomiting, diarrhea, nausea, constipation, abdominal pain, upper abdominal pain, dry mouth,

dyspepsia, flatulence, tongue discoloration may occur.[36]

Endocrine

The drug may cause adrenal insufficiency so the level of the adrenocortical hormones should be monitored while taking it.[13][36] Oral ketoconazole at a dosage range of 400 to 2,000 mg/day has been found to result in a rate of gynecomastia of 21%.[37]

Liver

In July 2013, the US Food and Drug Administration (FDA) issued a warning that taking ketoconazole by mouth can cause severe liver injuries and adrenal gland problems: adrenal insufficiency and worsening of other related to the gland conditions.[13] It recommends oral tablets should not be a first-line treatment for any fungal infection. It should be used for the treatment of certain fungal infections, known as endemic mycoses, only when alternative antifungal therapies are not available or tolerated.[13] As contraindication it should not be used in people with acute or chronic liver disease.[13]

Hypersensitivity

Anaphylaxis after the first dose may occur.[medical citation needed] Other cases of hypersensitivity include urticaria.[11][6]

Topical formulations

The topical formulations 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 ketoconazole tablets, which are taken by mouth.[13]

Pregnancy

Ketoconazole is categorized as

pregnancy category C in the US.[38] Research in animals has shown it to cause teratogenesis when administered in high doses.[38] A subsequent trial in Europe failed to show a risk to infants of mothers receiving ketoconazole.[39]

Overdose

In the event of an

Activated charcoal may be administered within the first hour following overdose of oral ketoconazole.[6]

Interactions

The concomitant use of the following medications is contraindicated with ketoconazole tablets:[6][36]

And is not recommended:[6][36]

Ritonavir is known for increasing activity of the ketoconazole so it is recommended to reduce dosage.[6]

There is also a list of drugs which significantly decrease systemic exposure to the ketoconazole and drugs whose systemic exposure is increased by the ketoconazole.[6][36]

Pharmacology

Pharmacodynamics

Antifungal activity

As an antifungal, ketoconazole is structurally similar to

affinity
for fungal cell membranes.

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.[40][41]

Antihormonal activity

As an

precursors of testosterone.[25] Due to its efficacy at reducing systemic androgen levels, ketoconazole has been used with some success as a treatment for androgen-dependent prostate cancer.[43] 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.[44]

Ketoconazole, along with miconazole, has been found to act as an antagonist of the glucocorticoid receptor.[45][46]

Ketoconazole is a

11β-hydroxylase (IC50 values of 0.152 and 0.608 μM, respectively). Both isomers were relatively weak inhibitors of human placental aromatase.[9]

Oral ketoconazole has been used clinically as a steroidogenesis inhibitor in men, women, and children at dosages of 200 to 1,200 mg/day.

endogenous corticosteroids, such as cortisol, corticosterone, and aldosterone, as well as vitamin D.[54][48]

Ketoconazole 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.[48]

Other activities

Ketoconazole has been found to inhibit the activity of the cation channel TRPM5.[55]

Pharmacokinetics

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.[56] Ketoconazole is very lipophilic and tends to accumulate in fatty tissues.

Chemistry

Ketoconazole is a

synthetic imidazole.[57][58] It is a nonsteroidal compound.[57][58] It is a racemic mixture of two enantiomers, levoketoconazole ((2S,4R)-(−)-ketoconazole) and dextroketoconazole ((2R,4S)-(+)-ketoconazole).[57][58] Levoketoconazole is under development for potential clinical use as a steroidogenesis inhibitor with better tolerability and less toxicity than ketoconazole. Other steroidogenesis inhibitors besides ketoconazole and levoketoconazole include the nonsteroidal compound aminoglutethimide and the steroidal compound abiraterone acetate.[citation needed
]

History

Ketoconazole was discovered in 1976 at

mycoses.[61]

Due to incidence of serious

liver toxicity, the use of oral ketoconazole was suspended in France in July 2011, following review.[18] This event triggered an evaluation of oral ketoconazole throughout the rest of the European Union.[18][62] In 2013, oral ketoconazole was withdrawn in the European Union and Australia, and strict restrictions were placed on the use of oral ketoconazole in the United States and Canada.[18] Oral ketoconazole is indicated for use in these countries when the indication is a severe or life-threatening systemic infection and alternatives are unavailable.[18] However, topical ketoconazole, which does not distribute systemically, is safe and widely used still.[18]

Ketoconazole HRA was approved for use in the European Union for treatment of Cushing's syndrome in November 2013.[7][63]

Society and culture

Generic names

Ketoconazole is the

INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name, and JANTooltip Japanese Accepted Name.[57][58][64][65]

Brand names

Ketoconazole has been marketed under a large number of brand names.[57][58][64][65]

Availability

Ketoconazole is available widely throughout the world.[58][65]

In 2013, the European Medicines Agency's Committee for 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.[66]

Research

As of March 2019, oral levoketoconazole (developmental code name COR-003, tentative brand name Recorlev) is phase III clinical trials for the treatment of Cushing's syndrome.[67] Oral levoketoconazole may have a lower risk of liver toxicity than oral ketoconazole.[68]

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.[69]

References

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