 (2R,4S)-(+)-ketoconazole (top) (2S,4R)-(−)-ketoconazole (bottom) | |
-(%252B)-ketoconazole-from-xtal-3D-bs-17.png) Ball-and-stick model of (2R,4S)-(+)-ketoconazole | |
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| Pronunciation | /ˌkiːtoʊˈkoʊnəˌzoʊl,-zɒl/[1][2] |
| Trade names | Nizoral, others |
| Other names | R-41400; KW-1414 |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682816 |
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| Routes of administration | By mouth (tablets),topical (cream,shampoo,solution) |
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| Pharmacokinetic data | |
| Bioavailability | By mouth: 37–97%[7] |
| Protein binding | 84 to 99% |
| Metabolism | Extensiveliver (predominantly oxidation,O-dealkylation) |
| Metabolites | N-deacetyl ketoconazole |
| Eliminationhalf-life | Biphasic |
| Excretion | Bile duct (major) andkidney[8] |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.059.680 |
| Chemical and physical data | |
| Formula | C26H28Cl2N4O4 |
| Molar mass | 531.43 g·mol−1 |
| 3D model (JSmol) | |
| Chirality | Racemic mixture[8][9] |
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Ketoconazole, sold under the brand nameNizoral, among others, is anantiandrogen,antifungal, andantiglucocorticoid medication used to treat a number offungal infections.[10] Applied to the skin it is used forfungal skin infections such astinea,cutaneous candidiasis,pityriasis versicolor,dandruff, andseborrheic dermatitis.[11] Takenby mouth it is a less preferred option and recommended for only severe infections when other agents cannot be used.[10] Other uses include treatment ofexcessive male-patterned hair growth in women andCushing's syndrome.[10]
Commonside effects whenapplied to the skin include redness.[11] Common side effects when taken by mouth includenausea,headache, andliver problems.[10] Liver problems may result in death or the need for aliver transplantation.[10][12] Other severe side effects when taken orally includeQT prolongation,adrenocortical insufficiency, andanaphylaxis.[10][12] It is animidazole and works by hindering the production ofergosterol required for the fungalcell membrane, thereby slowing growth.[10]
Ketoconazole was patented in 1977 by Belgian pharmaceutical companyJanssen, and came into medical use in 1981.[13] It is available as ageneric medication and formulations that are applied to the skin areover the counter in theUnited Kingdom.[11] In 2023, it was the 140th most commonly prescribed medication in the United States, with more than 3 million prescriptions.[14][15] The formulation that is taken by mouth waswithdrawn in the European Union and in Australia in 2013,[16][17] and in China in 2015.[18] In addition, its use was restricted in the United States and Canada in 2013.[17]
Topically administered ketoconazole is usually prescribed for fungal infections of the skin and mucous membranes, such asathlete's foot,ringworm,candidiasis (yeast infection or thrush),jock itch, andtinea versicolor.[19] Topical ketoconazole is also used as a treatment fordandruff (seborrheic dermatitis of the scalp) and forseborrheic dermatitis on other areas of the body, perhaps acting in these conditions by suppressing levels of the fungusMalassezia furfur on the skin.[19][20][21]
Ketoconazole has activity against many kinds of fungi that may cause human disease, such asCandida,Histoplasma,Coccidioides, andBlastomyces (although it is not active againstAspergillus),chromomycosis andparacoccidioidomycosis.[22][12] First made in 1977,[19] ketoconazole was the first orally-activeazole antifungal medication.[22] However, ketoconazole has largely been replaced as a first-line systemic antifungal medication by otherazole antifungal agents, such asfluconazole and/oritraconazole, because of ketoconazole's greater toxicity, poorer absorption, and more limited spectrum of activity.[22][23]
Ketoconazole is used orally in dosages of 200 to 400 mg per day in the treatment of superficial and deep fungal infections.[24]
Ketoconazole shampoo in conjunction with an oral5α-reductase inhibitor such asfinasteride ordutasteride has been used off label to treatandrogenic alopecia. It was speculated that antifungal properties of ketoconazole reduce scalp microflora and consequently may reduce follicular inflammation that contributes to alopecia.[25]
Limited clinical studies suggest ketoconazole shampoo used either alone[26][27] or in combination with other treatments[28] may be useful in reducing hair loss in some cases.[29]
The side effects of ketoconazole are sometimes harnessed in the treatment of non-fungal conditions. While ketoconazole blocks the synthesis of the sterolergosterol in fungi, in humans, at high dosages (>800 mg/day), it potently inhibits the activity of severalenzymes necessary for the conversion ofcholesterol tosteroid hormones such astestosterone andcortisol.[22][24] Specifically, ketoconazole has been shown to inhibitcholesterol side-chain cleavage enzyme, which converts cholesterol topregnenolone,17α-hydroxylase and17,20-lyase,[24] which convertpregnenolone intoandrogens, and11β-hydroxylase, which converts11-deoxycortisol tocortisol.[30] All of these enzymes are mitochondrialcytochrome p450 enzymes.[31] Based on theseantiandrogen andantiglucocorticoid effects, ketoconazole has been used with some success as a second-line treatment for certain forms of advancedprostate cancer[24][32] and for the suppression ofglucocorticoid synthesis in the treatment ofCushing's syndrome.[33] However, in the treatment of prostate cancer, concomitant glucocorticoid administration is needed to preventadrenal insufficiency.[24] Ketoconazole has additionally been used, in lower dosages, to treathirsutism and, in combination with aGnRH analogue,male-limited precocious puberty.[24] In any case, the risk ofhepatotoxicity with ketoconazole limits its use in all of these indications, especially in those that are benign such as hirsutism.[24]
Ketoconazole has been used to prevent thetestosterone flare at the initiation ofGnRH agonist therapy in men with prostate cancer.[34]
Oral ketoconazole has variouscontraindications, such as concomitant use with certain other drugs due to knowndrug interactions.[5] Other contraindications of oral ketoconazole includeliver disease,adrenal insufficiency, and knownhypersensitivity to oral ketoconazole.[5]
Vomiting, diarrhea, nausea, constipation, abdominal pain, upper abdominal pain, dry mouth,dysgeusia,dyspepsia,flatulence, tongue discoloration may occur.[35]
The drug may causeadrenal insufficiency so the level of theadrenocortical hormones should be monitored while taking it.[12][35] Oral ketoconazole at a dosage range of 400 to 2,000 mg/day has been found to result in a rate ofgynecomastia of 21%.[36]
In July 2013, the USFood and Drug Administration (FDA) issued a warning that taking ketoconazole by mouth can cause severe liver injuries andadrenal gland problems:adrenal insufficiency and worsening of other diseases related to the gland conditions.[12] 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 alternativeantifungal therapies are not available or not tolerated.[12] As contraindication it should not be used in people with acute orchronic liver disease.[12]
Anaphylaxis after the first dose may occur.[medical citation needed] Other cases of hypersensitivity includeurticaria.[10][5]
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.[12]
Ketoconazole is categorized aspregnancy category C(Risk not ruled out) in the US.[37] Research in animals has shown it to causeteratogenesis when administered in high doses.[37] A subsequent trial in Europe failed to show a risk toinfants of mothers receiving ketoconazole.[38]
In the event of anoverdose of oral ketoconazole, treatment should be supportive and based onsymptoms.[5]Activated charcoal may be administered within the first hour following overdose of oral ketoconazole.[5]
Theconcomitant use of the following medications are contraindicated with ketoconazole tablets:[5][35]
The following medications are not recommended with ketoconazole:[5][35]
Ritonavir(anantiretrovial medication), is known for increasing the activity of ketoconazole. So it is recommended to reduce dosage.[5]
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.[5][35]
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As an antifungal, ketoconazole is structurally similar toimidazole, and interferes with the fungal synthesis ofergosterol, a constituent of fungalcell membranes, as well as certainenzymes. As with allazole antifungal agents, ketoconazole works principally by inhibiting theenzymecytochrome P45014α-demethylase (CYP51A1).[31] This enzyme participates in thesterolbiosynthesis pathway that leads fromlanosterol toergosterol. Lower doses offluconazole anditraconazole are required to kill fungi compared to ketoconazole, as they have been found to have a greateraffinity for fungal cell membranes.
Resistance to ketoconazole has been observed in a number of clinical fungal isolates, includingCandida 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.[39][40]
As anantiandrogen, ketoconazole operates through at least twomechanisms 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.[24][41] It produces this effect through inhibition of17α-hydroxylase and17,20-lyase, which are involved in the synthesis and degradation of steroids, including theprecursors oftestosterone.[24] Due to its efficacy at reducing systemic androgen levels, ketoconazole has been used with some success as a treatment for androgen-dependent prostate cancer.[42] Second, ketoconazole is anandrogen receptorantagonist, competing with androgens such as testosterone anddihydrotestosterone (DHT) for binding to theandrogen receptor. This effect is thought to be quite weak however, even with high oral doses of ketoconazole.[43]
Ketoconazole, along withmiconazole, has been found to act as anantagonist of theglucocorticoid receptor.[44][45]
Ketoconazole is aracemic mixture consisting ofcis-(2S,4R)-(−) andcis-(2R,4S)-(+) enantiomers.[9] Thecis-(2S,4R) isomer was more potent in inhibitingprogesterone 17α,20-lyase than its enantiomer (IC50 values of 0.05 and 2.38μM, respectively) and in inhibiting11β-hydroxylase (IC50 values of 0.152 and 0.608μM, respectively). Both isomers were relatively weak inhibitors of human placentalaromatase.[8]
Oral ketoconazole has been used clinically as a steroidogenesis inhibitor in men, women, and children at dosages of 200 to 1,200 mg/day.[46][47][48] Numerous small studies have investigated the effects of oral ketoconazole on hormone levels in humans.[49] It has been found in men to significantly decrease testosterone and estradiol levels and to significantly increaseluteinizing hormone,progesterone, and17α-hydroxyprogesterone levels, whereas levels ofandrostenedione,follicle-stimulating hormone, andprolactin were unaffected.[49][50][47] 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.[49] Better effects on suppression of testosterone levels have been observed in men when ketoconazole is combined with aGnRH agonist to suppress thehypothalamic–pituitary–gonadal axis, which prevents compensatory upregulation of luteinizing hormonesecretion and consequent activation of gonadal testosterone production.[47] Inpremenopausal women withpolycystic ovary syndrome, ketoconazole has been found to significantly decrease levels of androstenedione and testosterone and significantly increase levels of 17α-hydroxyprogesterone and estradiol.[48][51] Studies inpostmenopausal women with breast cancer have found that ketoconazole significantly decreases androstenedione levels, slightly decreasesestradiol levels, and does not affectestrone levels.[52] This indicates minimal inhibition of aromatase by ketoconazolein vivo in humans.[52] Ketoconazole has also been found to decrease levels ofendogenouscorticosteroids, such ascortisol,corticosterone, andaldosterone, as well asvitamin D.[53][47]
Ketoconazole has been found to displacedihydrotestosterone and estradiol fromsex hormone-binding globulinin vitro, but this was not found to be relevantin vivo.[47]
Ketoconazole has been found to inhibit the activity of the cation channelTRPM5.[54]
When administered orally, ketoconazole is best absorbed at highlyacidic levels, soantacids or other causes of decreasedstomach acid levels will lower the drug's absorption. Absorption can be increased by taking it with an acidic beverage, such ascola.[55] Ketoconazole is verylipophilic and tends to accumulate in fatty tissues.
Ketoconazole is asyntheticimidazole.[56][57] It is anonsteroidal compound.[56][57] It is aracemic mixture of twoenantiomers,levoketoconazole ((2S,4R)-(−)-ketoconazole) and dextroketoconazole ((2R,4S)-(+)-ketoconazole).[56][57] Levoketoconazole is under development for potential clinical use as asteroidogenesis inhibitor with bettertolerability and lesstoxicity than ketoconazole. Other steroidogenesis inhibitors besides ketoconazole andlevoketoconazole include the nonsteroidal compoundaminoglutethimide and thesteroidal compoundabiraterone acetate.[citation needed]
Ketoconazole was discovered in 1976 atJanssen Pharmaceuticals.[58] It waspatented in 1977,[13] followed by introduction in theUnited States in July 1981.[17][7][59][13] Following its introduction, ketoconazole was the only systemic antifungal available for almost a decade.[17] Ketoconazole was introduced as the prototypical medication of the imidazole group of antifungals.[60] Oral ketoconazole has been replaced with oralfluconazole oritraconazole for manymycoses.[60]
Due to incidence of seriousliver toxicity, the use of oral ketoconazole was suspended in France in July 2011, following review.[17] This event triggered an evaluation of oral ketoconazole throughout the rest of the European Union.[17][61] 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.[17] Oral ketoconazole is indicated for use in these countries when the indication is a severe or life-threatening systemic infection and alternatives are unavailable.[17] However, topical ketoconazole, which does not distribute systemically, is safe and widely used still.[17]
Ketoconazole HRA was approved for use in the European Union for treatment ofCushing's syndrome in November 2013.[6][62]
Ketoconazole is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name,BANTooltip British Approved Name, andJANTooltip Japanese Accepted Name.[56][57][63][64]
Ketoconazole has been marketed under a large number of brand names.[56][57][63][64]
Ketoconazole is available widely throughout the world.[57][64]
In 2013, theEuropean Medicines Agency'sCommittee 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 seriousliver injury from systemic ketoconazole outweighs its benefits.[65]
As of March 2019, orallevoketoconazole (developmental code name COR-003, tentative brand name Recorlev) isphase IIIclinical trials for the treatment ofCushing's syndrome.[66] Oral levoketoconazole may have a lower risk of liver toxicity than oral ketoconazole.[67]
Ketoconazole is sometimes prescribed as an antifungal byveterinarians for use in pets, often as unflavored tablets that may need to be cut to smaller size for correct dosage.[68]
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