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Ketoconazole is a synthetic imidazole-class antifungal medication, first developed by Janssen Pharmaceutica NV. It works by inhibiting the synthesis of ergosterol, a key component of fungal cell membranes, to stop fungal growth or kill pathogens. It has both oral and topical formulations, used for a range of superficial and systemic fungal infections, as well as some off-label endocrine conditions.
Key moments
1978First synthesized by Janssen Pharmaceutica
June 1981First approved by US FDA for clinical use
Late 20th centuryWidely marketed under brand names like Nizoral for various fungal indications
Clinical Status and Shifting Use
Ketoconazole was the first oral broad-spectrum antifungal approved by the FDA, but its oral use has declined in many regions due to safety concerns including hepatotoxicity and endocrine disruptions. Topical formulations (creams, shampoos) remain common for treating dandruff, tinea infections, and vaginal candidiasis. It also sees limited off-label use for treating Cushing's syndrome by inhibiting cortisol synthesis.
Mechanism and Classification
As a CYP51 inhibitor, it targets fungal lanosterol 14α-demethylase, blocking ergosterol production. It belongs to the imidazole class of antifungals, alongside miconazole and clotrimazole, though its systemic use has been largely replaced by newer agents like voriconazole with better safety profiles.
Brand and Generic Landscape
While originally developed as a branded drug (Nizoral), ketoconazole is now available as a generic medication worldwide. Its topical formulations are still widely sold over-the-counter in many countries for skin and scalp fungal issues.
medlineplus
a682816
dailymedid
Ketoconazole
pregnancy au
B3
routes of administration
By mouth (tablets), topical (cream, shampoo, solution)
Ketoconazole, sold under the brand name Nizoral, among others, is an antiandrogen, antifungal, and antiglucocorticoid medication used to treat a number of fungal infections.[5] Applied to the skin it is used for fungal skin infections such as tinea, cutaneous candidiasis, pityriasis versicolor, dandruff, and seborrheic dermatitis.[6] Taken by mouth it is a less preferred option and recommended for only severe infections when other agents cannot be used.[5] Other uses include treatment of excessive male-patterned hair growth in women and Cushing's syndrome.[5]
Common side effects when applied to the skin include redness.[6] Common side effects when taken by mouth include nausea, headache, and liver problems.[5] Liver problems may result in death or the need for a liver transplantation.[5] Other severe side effects when taken orally include QT prolongation, adrenocortical insufficiency, and anaphylaxis.[5][7] It is an imidazole and works by hindering the production of ergosterol required for the fungal cell membrane, thereby slowing growth.[5]
Ketoconazole was patented in 1977 by Belgian pharmaceutical company Janssen, and came into medical use in 1981.[8] It is available as a generic medication and formulations that are applied to the skin are over the counter in the United Kingdom.[6] In 2023, it was the 140th most commonly prescribed medication in the United States, with more than 3million prescriptions.[9][10] The formulation that is taken by mouth was withdrawn in the European Union and in Australia in 2013,[11] and in China in 2015.[12] In addition, its use was restricted in the United States and Canada in 2013.[13]
Medical uses
Topical antifungal
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.[14] 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.[14][15][16]
Systemic antifungal
Contraindications
Oral ketoconazole has various contraindications, such as concomitant use with certain other drugs due to known drug interactions.Other contraindications of oral ketoconazole include liver disease, adrenal insufficiency, and known hypersensitivity to oral ketoconazole.
The drug may cause adrenal insufficiency so the level of the adrenocortical hormones should be monitored while taking it.[7] 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%.[31]
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
Overdose
In the event of an overdose of oral ketoconazole, treatment should be supportive and based on symptoms.Activated charcoal may be administered within the first hour following overdose of oral ketoconazole.
Interactions
The concomitant use of the following medications are contraindicated with ketoconazole tablets:[34][35]
The following medications are not recommended with ketoconazole:[34][35]
Ritonavir(an antiretrovial medication), is known for increasing the activity of ketoconazole.So it is recommended to reduce dosage.[34]
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.[34]
Pharmacology
Pharmacodynamics
Antifungal activity
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 enzymecytochrome P45014α-demethylase (CYP51A1).[27] This enzyme participates in the sterolbiosynthesis 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.
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.
Chemistry
Ketoconazole is a syntheticimidazole.It is a nonsteroidal compound.It is a racemic mixture of two enantiomers, levoketoconazole ((2S,4R)-(−)-ketoconazole) and dextroketoconazole ((2R,4S)-(+)-ketoconazole).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.
History
Ketoconazole was discovered in 1976 at Janssen Pharmaceuticals.[53] It was patented in 1977,[8] followed by introduction in the United States in July 1981.[13][54][55][8] Following its introduction, ketoconazole was the only systemic antifungal available for almost a decade.[13] Ketoconazole was introduced as the prototypical medication of the imidazole group of antifungals.
Society and culture
Generic names
Ketoconazole is the generic name of the drug and its INN, USAN, BAN, and JAN.[60][61][62][63]
Brand names
Ketoconazole has been marketed under a large number of brand names.[60]
Research
As of March 2019, oral levoketoconazole (developmental code name COR-003, tentative brand name Recorlev) is phase IIIclinical trials for the treatment of Cushing's syndrome.[65] Oral levoketoconazole may have a lower risk of liver toxicity than oral ketoconazole.[66]
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.[67]
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), chromomycosis and paracoccidioidomycosis.[17][7] First made in 1977,[14] ketoconazole was the first orally-active azole antifungal medication.[17] However, ketoconazole has largely been replaced as a first-line systemic antifungal medication by other azole antifungal agents, such as fluconazole and/or itraconazole, because of ketoconazole's greater toxicity, poorer absorption, and more limited spectrum of activity.[17][18]
Ketoconazole is used orally in dosages of 200 to 400 mg per day in the treatment of superficial and deep fungal infections.[19]
Off-label uses
Hair loss
Ketoconazole shampoo in conjunction with an oral 5α-reductase inhibitor such as finasteride or dutasteride has been used off label to treat androgenic alopecia.It was speculated that antifungal properties of ketoconazole reduce scalp microflora and consequently may reduce follicular inflammation that contributes to alopecia.[20]
Limited clinical studies suggest ketoconazole shampoo used either alone[21][22] or in combination with other treatments[23] may be useful in reducing hair loss in some cases.[24] However, one study found that applying a 2% Topical Ketoconazole solution on the balding scalps of women found comparable regrowth to 2% Minoxidil, albeit with a longer onset of action.[25]
Hormonal
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 humans, 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.[17][19] Specifically, ketoconazole has been shown to inhibit cholesterol side-chain cleavage enzyme, which converts cholesterol to pregnenolone, 17α-hydroxylase and 17,20-lyase,[19] which convert pregnenolone into androgens, and 11β-hydroxylase, which converts 11-deoxycortisol to cortisol.[26] All of these enzymes are mitochondrial cytochrome p450 enzymes.[27]
Hair loss
Ketoconazole shampoo in conjunction with an oral 5α-reductase inhibitor such as finasteride or dutasteride has been used off label to treat androgenic alopecia.It was speculated that antifungal properties of ketoconazole reduce scalp microflora and consequently may reduce follicular inflammation that contributes to alopecia.[20]
Limited clinical studies suggest ketoconazole shampoo used either alone[21][22] or in combination with other treatments[23] may be useful in reducing hair loss in some cases.[24] However, one study found that applying a 2% Topical Ketoconazole solution on the balding scalps of women found comparable regrowth to 2% Minoxidil, albeit with a longer onset of action.[25]
Hormonal
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 humans, 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.[17][19] Specifically, ketoconazole has been shown to inhibit cholesterol side-chain cleavage enzyme, which converts cholesterol to pregnenolone, 17α-hydroxylase and 17,20-lyase,[19] which convert pregnenolone into androgens, and 11β-hydroxylase, which converts 11-deoxycortisol to cortisol.[26] All of these enzymes are mitochondrial cytochrome p450 enzymes.[27] 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[19][28] and for the suppression of glucocorticoid synthesis in the treatment of Cushing's syndrome.[29] However, in the treatment of prostate cancer, concomitant glucocorticoid administration is needed to prevent adrenal insufficiency.[19] Ketoconazole has additionally been used, in lower dosages, to treat hirsutism and, in combination with a GnRH analogue, male-limited precocious puberty.[19] 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.[19]
Ketoconazole has been used to prevent the testosterone flare at the initiation of GnRH agonist therapy in men with prostate cancer.[30]
problems:
adrenal insufficiency
and worsening of other diseases related to the gland conditions.
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 not tolerated.[7] As contraindication it should not be used in people with acute or chronic liver disease.[7]
Hypersensitivity
Anaphylaxis after the first dose may occur.Other cases of hypersensitivity include urticaria.[5]
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.[7]
Pregnancy
Ketoconazole is categorized as pregnancy category C (Risk not ruled out) in the US.Research in animals has shown it to cause teratogenesis when administered in high doses.[32] A subsequent trial in Europe failed to show a risk to infants of mothers receiving ketoconazole.[33]
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.[36][37]
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. 400 mg three times per day) block both testicular and adrenal androgen biosynthesis, leading to a reduction in circulating testosterone levels.[19][38] 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.[19] Due to its efficacy at reducing systemic androgen levels, ketoconazole has been used with some success as a treatment for androgen-dependent prostate cancer.[39] Second, ketoconazole is an androgen receptorantagonist, 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.[40]
Ketoconazole, along with miconazole, has been found to act as an antagonist of the glucocorticoid receptor.[41][42]
Ketoconazole is a racemic mixture consisting of cis-(2S,4R)-(−) and cis-(2R,4S)-(+) enantiomers.[2] 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.[1]
Oral ketoconazole has been used clinically as a steroidogenesis inhibitor in men, women, and children at dosages of 200 to 1,200 mg/day.[43][44] Numerous small studies have investigated the effects of oral ketoconazole 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.[45][46] The ratio of testosterone to estradiol is also decreased during oral ketoconazole therapy in men.[47] Suppression of testosterone levels by ketoconazole is generally partial and has often been found to be transient.[45] Better effects on suppression of testosterone levels have been observed in men when ketoconazole is combined with a
Ketoconazole has been found to displace dihydrotestosterone and estradiol from sex hormone-binding globulinin vitro, but this was not found to be relevant in vivo.[47]
Other activities
Ketoconazole has been found to inhibit the activity of the cation channel TRPM5.[51]
Antifungal activity
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 enzymecytochrome P45014α-demethylase (CYP51A1).[27] This enzyme participates in the sterolbiosynthesis 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.
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.[36][37]
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. 400 mg three times per day) block both testicular and adrenal androgen biosynthesis, leading to a reduction in circulating testosterone levels.[19][38] 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.[19] Due to its efficacy at reducing systemic androgen levels, ketoconazole has been used with some success as a treatment for androgen-dependent prostate cancer.[39] Second, ketoconazole is an androgen receptorantagonist, 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.[40]
Ketoconazole, along with miconazole, has been found to act as an antagonist of the glucocorticoid receptor.[41][42]
Ketoconazole is a racemic mixture consisting of cis-(2S,4R)-(−) and cis-(2R,4S)-(+) enantiomers.[2] 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.[1]
Oral ketoconazole has been used clinically as a steroidogenesis inhibitor in men, women, and children at dosages of 200 to 1,200 mg/day.[43][44] Numerous small studies have investigated the effects of oral ketoconazole 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.[45][46] The ratio of testosterone to estradiol is also decreased during oral ketoconazole therapy in men.[47] Suppression of testosterone levels by ketoconazole is generally partial and has often been found to be transient.[45] Better effects on suppression of testosterone levels have been observed in men when ketoconazole is combined with a GnRH agonist
Ketoconazole has been found to displace dihydrotestosterone and estradiol from sex hormone-binding globulinin vitro, but this was not found to be relevant in vivo.[47]
Other activities
Ketoconazole has been found to inhibit the activity of the cation channel TRPM5.[51]
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.[52] Ketoconazole is very lipophilic and tends to accumulate in fatty tissues.
Due to incidence of serious liver toxicity, the use of oral ketoconazole was suspended in France in July 2011, following review.[13] This event triggered an evaluation of oral ketoconazole throughout the rest of the European Union.[13][57] 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.[13] Oral ketoconazole is indicated for use in these countries when the indication is a severe or life-threatening systemic infection and alternatives are unavailable.[13] However, topical ketoconazole, which does not distribute systemically, is safe and widely used still.[13]
Ketoconazole HRA was approved for use in the European Union for treatment of Cushing's syndrome in November 2013.[58][59]
Ketoconazole is available widely throughout the world.[61][63]
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.[64]
23.Comparative efficacy of various treatment regimens for androgenetic alopecia in men The Journal of Dermatology, August 2002^
24.Topical Antiandrogen Therapies for Androgenetic Alopecia and Acne Vulgaris Am J Clin Dermatol, December 2019^
25.Trichogenic effect of topical ketoconazole versus minoxidil 2% in female pattern hair loss: A clinical and trichoscopic evaluation Biomedical Dermatology, 2019^
26.MedScape Ectopic Cortisol Production Derived From Malignant Testicular Masses: Treatment and Management, Nature Publishing Group, retrieved 18 April 2015^
27.Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes The Journal of Clinical Investigation, May 1983^
28.Cancer: Principles & Practice of Oncology Lippincott Williams & Wilkins, 2008^
29.Use of ketoconazole in the treatment of Cushing's syndrome The Journal of Clinical Endocrinology and Metabolism, December 1986^
30.Flare Associated with LHRH-Agonist Therapy Reviews in Urology, 2001^
31.Drug-induced gynecomastia: an evidence-based review Expert Opinion on Drug Safety, September 2012^
36.Clinically significant azole cross-resistance in Candida isolates from HIV-positive patients with oral candidosis AIDS, December 1997^
37.Cloning of Candida albicans genes conferring resistance to azole antifungal agents: characterization of CDR2, a new multidrug ABC transporter gene Microbiology, February 1997^
38.Ketoconazole high dose in management of hormonally pretreated patients with progressive metastatic prostate cancer. Dutch South-Eastern Urological Cooperative Group Urology, May 1989^
39.P450-dependent enzymes as targets for prostate cancer therapy The Journal of Steroid Biochemistry and Molecular Biology, January 1996^
41.Ketoconazole binds to glucocorticoid receptors and exhibits glucocorticoid antagonist activity in cultured cells The Journal of Clinical Investigation, July 1983^
42.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 Molecular Pharmacology, July 2006^
43.Antiandrogen therapy in dermatology International Journal of Dermatology, November 1996^
44.Reproductive Endocrinology and Infertility Springer, 2010^
45.Impacts of Medications on Male Fertility Springer, 2017^
46.Ketoconazole and other imidazole derivatives as inhibitors of steroidogenesis Endocrine Reviews, November 1986^
47.The endocrine effects of ketoconazole Journal of Endocrinological Investigation, August 1986^
48.Low dose ketoconazole attenuates serum androgen levels in patients with polycystic ovary syndrome and inhibits ovarian steroidogenesis in vitro Fertility and Sterility, May 1994^
49.New endocrine drugs for treatment of advanced breast cancer Acta Oncologica, 2009^
50.Chemotherapy of Fungal Diseases Springer, 1990^
51.2+-Activated Monovalent Cation-Selective Channels SLAS Discovery, April 2018^
52.Effects of an acidic beverage (Coca-Cola) on absorption of ketoconazole Antimicrobial Agents and Chemotherapy, August 1995^
53.Antimycotic imidazoles. part 4. Synthesis and antifungal activity of ketoconazole, a new potent orally active broad-spectrum antifungal agent Journal of Medicinal Chemistry, August 1979^
, ketoconazole has been found to significantly decrease levels of androstenedione and testosterone and significantly increase levels of 17α-hydroxyprogesterone and estradiol.
, ketoconazole has been found to significantly decrease levels of androstenedione and testosterone and significantly increase levels of 17α-hydroxyprogesterone and estradiol.
