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Home> Encyclopedia >Pharmaceutical Intermediates>Antineoplastic Agents>Pharmaceutical
Ketoconazole structure
Ketoconazole structure


Iupac Name:2,2,2-trideuterio-1-[4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]ethanone
CAS No.: 65277-42-1
Molecular Weight:534.452
Modify Date.: 2023-02-01 14:15
Introduction: It is antifungal drug for being used to treat athlete's foot and excessive dandruff. View more+
1. Names and Identifiers
1.1 Name
1.2 Synonyms

(±)-Ketoconazole ,3-dioxolan-4-yl)methoxy)phenyl)-,cis- Brizoral cis-1-acetyl-4-(4-((2-(2,4-dichlorophenyl)-2-(1h-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl)methoxy)phenyl)piperazine Ethanone, 1-[4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]-, rel- Fungarest Fungoral ketoconazol Ketoderm Ketoisdin Ketozoral kw-1414 Micosin Nizaral Nizoral Nizral Onofin K Orifungal M Panfungol Phytorol Piperazine, 1-acetyl-4-[4-[[(2R,4S)-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-, rel- Piperazine, 1-acetyl-4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-, cis- R 41400 rel-1-[4-[4-[[(2R,4S)-2-(2,4-Dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]ethanone Tocon

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1.3 CAS No.
1.4 CID
1.6 Molecular Formula
C26H28Cl2N4O4 (isomer)
1.7 Inchi
1.8 InChIkey
1.9 Canonical Smiles
1.10 Isomers Smiles
2. Properties
2.1 Density
139.11 cm3
2.1 Melting point
2.1 Boiling point
753.4 °C at 760 mmHg
2.1 Refractive index
-10.5 ° (C=0.4, CHCl3)
2.1 Flash Point
409.4 °C
2.1 Precise Quality
2.1 PSA
2.1 logP
2.1 Solubility
methanol: soluble50mg/mL
2.2 AnalyticLaboratory Methods
Analyte: ketoconazole;; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards
2.3 Appearance
white to off white crystalline powder
2.4 Storage
Store at -20°C.
2.5 Color/Form
2.6 Decomposition
When heated to decomposition it emits toxic fumes of /hydrogen chloride; and nitrogen oxides/.
2.7 Physical
2.8 pKa
pKa 3.25/6.22(H2O,t =25,I=0.025) (Uncertain)
2.9 Water Solubility
Soluble in DMSO, ethanol, chloroform, water, and methanol.
2.10 Stability
Stable at room temperature in closed containers under normal storage and handling conditions.
2.11 StorageTemp
2.12 Toxicity Summary
IDENTIFICATION AND USE: Ketokonazole is used as antifungal medication. HUMAN EXPOSURE AND TOXICITY: Transient increases in serum AST, ALT, and alkaline phosphatase concentrations may occur during ketoconazole; therapy. Serious hepatotoxicity has occurred in patients receiving oral ketoconazole;, including cases that were fatal or required liver transplantation. Hepatotoxicity may be hepatocellular (in most cases), cholestatic, or a mixed pattern of injury. Although ketoconazole;-induced hepatotoxicity usually is reversible following discontinuance of the drug, recovery may take several months and rarely death has occurred. Symptomatic hepatotoxicity usually is apparent within the first few months of ketoconazole; therapy, but occasionally may be apparent within the first week of therapy. Some patients with ketoconazole;-induced hepatotoxicity had no obvious risk factors for liver disease. Serious hepatotoxicity has been reported in patients receiving high oral ketoconazole; dosage for short treatment durations and in patients receiving low oral dosage of the drug for long durations. Many of the reported cases of hepatotoxicity occurred in patients who received the drug for the treatment of tinea unguium (onychomycosi or the treatment of chronic, refractory dermatophytoses. Ketoconazole;-induced hepatitis has been reported in some children. Usual dosages (ie, 200-400 mg daily) of ketoconazole; have been reported to transiently (for 2-12 hours) inhibit testicular testosterone; synthesis. A compensatory increase in serum luteinizing hormone (LH) concentrations may occur. Dosages of 800-1200 mg daily have been reported to have a more prolonged effect on testosterone; synthesis; in one study in males receiving these high dosages, serum testosterone; concentrations remained at a subnormal level (ie, less than 300 ng/dL) throughout the day in about 30% of those receiving 800 mg daily and in all of those receiving 1200 mg daily. Oligospermia, decreased libido, and impotence often occurred in these males and azoospermia occurred rarely. The drug apparently directly inhibits synthesis of adrenal steroids and testosterone; in vitro and in vivo. Ketoconazole; appears to inhibit steroid synthesis principally by blocking several P-450 enzyme systems (eg, 11beta-hydroxylase, C-17,20-lyase, cholesterol; side-chain cleavage enzyme). Overall the results show that many of the commonly used azole; fungicides act as endocrine disruptors in vivo, although the profile of action in vivo varies. As ketoconazole; is known to implicate numerous endocrine-disrupting effects in humans. ANIMAL STUDIES: After oral administration toxicity was manifested in mice, rats and guinea pigs by sedation, catalepsy, ataxia, tremors, convulsions and pre-lethal loss of the righting reflex at doses >320 mg/kg. In dogs, toxicity was manifested by diarrhea and vomiting at doses >80 mg/kg. Ketoconazole; has been administered by the oral (gavage) and intravenous routes to mice, rats, guinea pigs and dogs. Toxicity after intravenous administration was manifested by spasms, convulsions and dyspnea in rats, mice and guinea pigs; pre-lethal loss of the righting reflex occurred in mice and guinea pigs, and dogs. Toxicity in dogs was also manifested by licking and convulsions. In rats the overall incidence of and type of tumors was not significantly different between treated and control groups, except for high-dosed female rats who had a decrease of the overall tumor rate. In developmental studies in rats the incidence of stillborn fetuses increased from a control value of 0.5% to 32.7% in rats dosed with 40 mg/kg and cannibalization of young occurred in two litters. In mice a significant decline in sperm motility and density in cauda epididymis was noted. A sharp decline in fertility (50% negative) in ketoconazole; treated mice was observed. A significant reduction in the total protein and sialic acid contents of testes, epididymis, seminal vesicle and ventral prostate were noticed. The cholesterol; contents of testes were raised while fructose; contents of seminal vesicle were reduced significantly. The ketoconazole; treatment altered the biochemical milieu of the reproductive tract. In the rabbit, ketoconazole; produces evidence of maternal toxicity, embryotoxicity and teratogenicity at a high dose of 40 mg/kg/day. Ketoconazole; did not show any signs of mutagenic potential when evaluated using the dominant lethal mutation test or the Ames Salmonella microsomal activator assay. ECOTOXICITY STUDIES: Ketoconazole; induced CYP1A and CYP3A expression in rainbow trout. However, the most pronounced effect of ketoconazole; was a 60 to 90% decrease in CYP3A catalytic activities in rainbow trout and in killifish.
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3. Use and Manufacturing
3.1 GHS Classification
Signal: Danger
GHS Hazard Statements
H301: Toxic if swallowed [Danger Acute toxicity, oral]
H360F ***: May damage fertility [Danger Reproductive toxicity]
H373 **: Causes damage to organs through prolonged or repeated exposure [Warning Specific target organ toxicity, repeated exposure]
H400: Very toxic to aquatic life [Warning Hazardous to the aquatic environment, acute hazard]
H410: Very toxic to aquatic life with long lasting effects [Warning Hazardous to the aquatic environment, long-term hazard]

Precautionary Statement Codes
P201, P202, P260, P264, P270, P273, P281, P301+P310, P308+P313, P314, P321, P330, P391, P405, and P501
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3.2 Methods of Manufacturing
(0.4 mmol) was added to an oven-dried 15 mL sealed tube equipped with a magnetic stir bar with a magnetic stirrer.Sulfur powder (S8) (0.8 mmol), ethyl bromodifluoroacetate (1.0 mmol) in sodium hydroxymethanesulfinate (HOCH2SO2Na) (0.8 mmol) as a solventThe reaction was stirred at 100 C for 24 hours in a solution of N, N-dimethylacetamide (DMA) (2.0 mL).After the reaction is completed, the reaction mixture is cooled to room temperature. The mixture is saturated with brine and ethyl acetate.Ester solvent extraction, The combined organic layers were dried over anhydrous Na 2SO Flash column chromatography was performed using 300-400 mesh silica gel, and the crude mixture was purified by preparative TLC monitoring spotting.The product (I-32) was obtained as a yellow oil, yield 43%.Adding
3.3 Usage
It is antifungal drug for being used to treat athlete's foot and excessive dandruff.
4. Safety and Handling
4.1 Symbol
4.1 Hazard Codes
4.1 Signal Word
4.1 Risk Statements
4.1 Safety Statements
4.1 Exposure Standards and Regulations
The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl ketoconazole, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.
4.2 Packing Group
4.2 Octanol/Water Partition Coefficient
log Kow = 4.34
4.3 Hazard Class
4.3 Hazard Declaration
H301; H360F; H373; H410
4.3 DisposalMethods
SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.
UN 2811
4.4 Caution Statement
P201-P273-P301 + P310-P308 + P313-P501
4.4 Formulations/Preparations
Tablets as 0.2 g; 2% solutions, ointments, and cream preparations.
Trade Names: Candoral, Cetonax, Fitonal, Fungarest, Fungicil, Fungo-Hubber, Fungoral, Ketazol, Ketoderm, Ketoisdin, Ketonan, Ketoral, Micoral, Micotek, Micoticum, Nizoral, Nizshampoo, Oromycosal, Oronazol, Panfungol, Rofenid, Terzolin.
Topical: Cream 2% Ketoconazole, (Taro, Teva), Shampoo: 1 Nizoral A-D, (McNeil), 2% Nizoral, (McNeil).
Oral: Tablets: 200 mg Ketoconazole Tablets (scored), AAIPharma, Mutual, Mylan, Sidmak, Pliva, Taro, Teva, Torpharm); Nizoral ( with povidone; scored), (Janssen).
4.5 WGK Germany
4.5 Toxicity
LD50 in mice, rats, guinea pigs, dogs (mg/kg): 44, 86, 28, 49 i.v.; 702, 227, 202, 780 orally (Heel)

2.Hazard identification

2.1 Classification of the substance or mixture

Acute toxicity - Oral, Category 3

Specific target organ toxicity \u2013 repeated exposure, Category 2

Hazardous to the aquatic environment, short-term (Acute) - Category Acute 1

Hazardous to the aquatic environment, long-term (Chronic) - Category Chronic 1

Reproductive toxicity, Category 1B

2.2 GHS label elements, including precautionary statements

Signal word


Hazard statement(s)

H301 Toxic if swallowed

H410 Very toxic to aquatic life with long lasting effects

Precautionary statement(s)

P264 Wash ... thoroughly after handling.

P270 Do not eat, drink or smoke when using this product.

P260 Do not breathe dust/fume/gas/mist/vapours/spray.

P273 Avoid release to the environment.

P201 Obtain special instructions before use.

P202 Do not handle until all safety precautions have been read and understood.

P280 Wear protective gloves/protective clothing/eye protection/face protection.


P301+P310 IF SWALLOWED: Immediately call a POISON CENTER/doctor/\u2026

P321 Specific treatment (see ... on this label).

P330 Rinse mouth.

P314 Get medical advice/attention if you feel unwell.

P391 Collect spillage.

P308+P313 IF exposed or concerned: Get medical advice/ attention.


P405 Store locked up.


P501 Dispose of contents/container to ...

2.3 Other hazards which do not result in classification


9. Other Information
9.0 Antifungal drug
Ketoconazole is a broad-spectrum antifungal imidazole with commercially available product being under the trade name of Jindakening, Meikangling and keNing. It interferes with the activity of fungal cytochrome P-450 with a high selectivity, thus inhibiting the biosynthesis of ergosterol in fungal cell membrane. It is effective in treating both shallow, deep fungal infections and can inhibit both fungal growth and the transition from spores to mycelium to prevent the further infection. It has antifungal effect on Candida genus, Fonsecaea, Coccidioides, Histoplasma, Sporothrix spp and Trichophyton. Clinically, it is suitable for the treatment of ringworm, athlete's foot, and skin ringworm, tinea, jock itch, and thrush, tinea versicolor as well as cutaneous candidiasis.
Ketoconazole lotion, as a skin external use, is mainly used for clinical treatment and prevention of various kinds of infections caused by Malassezia such as tinea versicolor, seborrheic dermatitis and scalp pityriasis (dandruff), and can quickly alleviate the desquamation and itching caused by seborrheic dermatitis and scalp pityriasis.
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9.1 Pharmacological effects
1. Pharmacology: ketoconazole belongs to azole-class antifungal drugs and has antifungal activity against various kinds of genus of deep fungal infections such as Candida, Fonsecaea, Coccidioides, Histoplasma, Sporothrix spp as well as Trichophyton. However, this product has a relative weak activity against Aspergillus, Sporothrix schenckii as well as some species of Dermateaceae and Mucor. This product, through actively interfering with the activity of cytochrome P-450, is capable of inhibiting the biosynthesis of the major steroids-ergosterol of the fungal cell membrane. Therefore, it destroys the fungal cell membrane and changes its permeability, resulting in the leakage of important intracellular material. Ketoconazole can also inhibit the biosynthesis of fungal triglyceride and phospholipid biosynthesis, inhibit the activity of oxidase and peroxidase, causing accumulation of intracellular hydrogen peroxide which further leads to cell submicroscopic structural degeneration and necrosis. For candida albicans, it can also suppress the transition process from spores to aggressive mycelium.
2. Toxicology: Long-term animal toxicity experiments have showed that ketoconazole can significantly increase the level of alkaline phosphatase and cause liver cell degeneration.
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9.2 Pharmacokinetics
This product can be dissolved and absorbed in gastric acid. Upon the reduction of the acidity of gastric acid, its absorption can be reduced. Administration after meals can increase its absorption with the bioavailability of administration after meal being as high as 75%. After the single-dose oral administration of 200mg and 400mg, the peak plasma concentrations were 3.6 ± 1.65mg/L and 6.5 ± 1.44mg/L, respectively with the time for reaching peak being 1-4 hours. After the absorption, this product is widely distributed in the body and can reach the synovial fluid of inflammation, saliva, bile, urine, tendons, skin and soft tissue, feces and so on. It has a poor penetrating capability through the blood-brain barrier. In most cases, the drug concentration in the cerebrospinal fluid is less than 1mg/L. This product can also penetrate through the blood placental barrier. The binding rate of serum protein is about 90% or more with the elimination half-life being 6.5 to 9 hours. Some part of the drugs is subjected to metabolism in the liver through degradation into inactive imidazole ring and piperazine ring. The metabolites and prototype drug is mainly excreted through the bile. The drug excreted through the kidneys only accounts 13% of the administered dose, of which about 2% to 4% for drug prototype. The product can also be secreted into milk.
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9.3 Indications
Ketoconazole is suitable for treating the following systemic fungal infections:
1. Candidiasis, chronic mucocutaneous candidiasis, oral candidiasis infection, Candida urinary tract infections as well as chronic, recurrent vaginal candidiasis which can be cured by topical therapy.
2. Dermatitis blastomycosis.
3. Coccidioidomycosis.
4. Histoplasmosis.
5. Chromomycosis.
6. Paracoccidioidomycosis.
It can be used for treating fungal skin diseases, hair ringworm and tinea versicolor caused by fungi and yeasts. When local therapy or oral administration of griseofulvin is invalid, or griseofulvin is unacceptable in the treatment of severe refractory fungal skin infection, we can choose the treatment of this drug.
9.4 Side effects
External administration
1. Common erythema, burning, itching, stinging or other irritation, folliculitis, skin atrophy and thinning as well as telangiectasia.
2. It can be observed of dry skin, hirsutism, striae atrophicae and increased susceptibility to infection.
3. Long-term medication may cause cortex hyperthyroidism, manifested as hirsutism, acne, moon face, osteoporosis and other symptoms.
4. It can be occasionally observed of allergic contact dermatitis.
Side effects of oral administration
1. Hepatotoxicity: ketoconazole can cause increased serum aminotransferase (AST, ALT) level and is reversible. It can be occasionally observed of severe liver toxicity, primarily being liver cell type with the incidence being about 0.01%. The clinical manifestations include jaundice, dark urine, white-color faeces and abnormal fatigue, etc., these effects can usually resume after the withdrawal of the drug, but there are also cases of deaths; there are also cases of hepatitis in children.
2. Gastrointestinal reaction: nausea, vomiting and anorexia are common cases.
3. Gynecomastia and lack of semen; this is related to the effect of this product on suppression of the biosynthesis of testosterone and adrenal cortical hormone.
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9.5 Precautions
1. Take it with caution upon the following cases:
lack of gastric acid (may cause the reduction of the absorption of the product).
Alcoholism or liver damage (it can cause liver toxicity).
2.Before or during the treatment, the patients should be regularly subject to monitoring of liver function. Elevated serum aminotransferase may not be accompanied by symptoms of hepatitis, however, if the serum aminotransferase value continues to rise or increase, or associated with liver toxicity symptoms, we should discontinue ketoconazole treatment.
3. For simultaneous administration of cimetidine or furan thiamine, take them at least 2 hours after taking this drug.
4. This product can cause photosensitivity reactions. Therefore, during the medication, we should avoid prolonged exposure to bright light and can wear colored glasses. 5. It is not allowed to take alcoholic beverages while taking the drug. Pay attention if dizziness or drowsiness occurs.
5. Patients of renal dysfunction don’t need to be subject to reduced dose upon taking it.
6. Ketoconazole has a very poor capability of penetrating blood-brain barrier and is not suitable for the treatment of fungal meningitis. This product also has poor efficacy in treating Aspergillus, Mucor or maduromycosis and thus is also not suitable.
7. Interfere with the diagnosis: can cause elevated serum aminotransferase, can also cause increased level of hemobilirubin.
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9.6 Pregnant and lactating women
The product can penetrate through the blood placental barrier. Animal experiments have shown that the product can be teratogenic such as syndactylia, lack of finger (toe) and dystocia in rats. US FDA data has shown that the application of this drug in pregnant women should be classified into Class C, namely being toxic in animal studies but is lack of adequate information in human studies. Therefore, pregnant women should be avoided for using it. Ketoconazole can be secreted into breast milk. The administration of it for humans has not found any issues, but the product can increase the likelihood of the occurrence of neonatal kernicterus, lactating women should weigh both advantages and disadvantages for using it.
9.7 Chemical Properties
It is white crystalline powder with the melting point being 146 ℃ and insoluble in water.
9.8 Uses
It is antifungal drug for being used to treat athlete's foot and excessive dandruff.
9.9 Production method
Put the mixture containing 2.4 parts of 1-acetyl-4-(4-hydroxyphenyl) piperazine, 0.4 part of 78% sodium hydride, 75 parts of dimethyl sulfate, 22.5 parts of benzene at 40 ℃ for stirring of 1 hour, followed by addition of 4.2 parts of 2-(2,4-dichlorobenzyl-2-(1H-imidazol-1-yl-methyl)-1,3-dioxolane-4-ylmethyl methanesulfonate. Stir at 100 °C overnight with the reaction product resulting in 3.2 parts ketoconazole after treatment.
9.10 Description
Ketoconazole (Nizoral), an orally effective broadspectrum antifungal agent, blocks hydroxylating enzyme systems by interacting with cytochrome P450 at the heme iron site to inhibit steroid and/or androgen synthesis in adrenals, gonads, liver, and kidney. The most sensitive site of action appears to be the C17-20 lyase reaction involved in the formation of sex steroids. This explains the greater suppressibility of testosterone production than with cortisol. Cholesterol side-chain cleavage and 11β/18-hydroxylase are secondary sites of inhibition.
9.11 Chemical Properties
White or almost white powder.
9.12 Originator
9.13 Uses
antifungal, PXR/SRC1 & CAR/SRC1 inhibitor
9.14 Uses
An inhibitor of CYP proteins, thromboxane synthetase, and 5-LO
9.15 Uses
Inhibits cytochrome P-450 dependent steps in the biosynthesis of steroid hormones in vivo. Antimetastatic and antineoplastic activity. Orally active 5-lipoxygenase and thromboxane synthase inhibitor
9.16 Indications
Ketoconazole (Nizoral) is approved for treating dermatophyte infections unresponsive to griseofulvin and for patients unable to tolerate that drug. It is a broad-spectrum antifungal agent that in very high doses inhibits several steps in the biosynthesis of both adrenal and gonadal steroids. While the normal antifungal dose is 200 mg/day, testosterone biosynthesis in both the adrenal and testis is completely abolished by doses of 800 to 1,600 mg/day. This drug is used most commonly for large virilizing adrenal tumors that cannot be surgically removed.
9.17 Brand name
Ketozole (Taro); Nizoral (Janssen); Nizoral (McNeil);Cerozalol;Cetonax;Fetonal;Fungarol;Fungo-hubber;Ketocidin;Ketoisdin;Ketonan;Ketoral;Micoral;Micotek;Micoticum;Nizcrem;Nizoral 2% shampoo;Nizoral 20% cream;Nizovules;Nizshampoo;Oromycosal;Oronazol;Panfungol;Rofenid;Spike;Unidox.
9.18 Therapeutic Function
9.19 World Health Organization (WHO)
Ketoconazole, an imidazole antifungal agent, was introduced in 1978 for the topical and systemic treatment of a wide variety of fungal infections. Its use by mouth has been associated with hepatotoxicity, including cases of hepatitis, which have usually been reversible on discontinuation of the drug, but some fatalities have also occurred. Ketoconazole is widely marketed.
9.20 Antimicrobial activity
The spectrum includes dermatophytes, some dimorphic fungi and Candida spp.
9.21 Acquired resistance
Resistance has been documented in patients treated for chronic mucocutaneous candidosis and AIDS patients with oropharyngeal or esophageal candidosis. Some fluconazoleresistant C. albicans and C. glabrata are cross-resistant to ketoconazole.
9.22 General Description
Ketoconazole is an imidazole antifungal agent administered through topical or oral means. It is used for the treatment of chronic mucocutaneous candidiasis, fungal infections of the gastro-intestinal tract, dermatophyte infections, systemic infections, and fungal infections in immuno-compromised patients.
9.23 Pharmaceutical Applications
A synthetic dioxolane imidazole available for oral and topical use.
9.24 Biological Activity
Antifungal agent; potent inhibitor of cytochrome P450c17.
9.25 Biochem/physiol Actions
Ketoconazole is an imidazole derivative. It plays an important role in inhibiting the conversion of lanosterol to ergosterol in the cell wall of fungi. Ketoconazole has therapeutic effects against dermatophytosis, superficial candidiasis, and paracoccidioidomycosis.
9.26 Mechanism of action
Ketoconazole has little effect on Aspergillus or Cryptococcus. Ketoconazole is highly dependent on low stomach pH for absorption, and antacids or drugs that raise stomach pH will lower the bioavailability of ketoconazole. As with other azoles, it is extensively metabolized by microsomal enzymes. All the metabolites are inactive. Evidence that CYP3A4 plays a significant role in metabolism of ketoconazole is that coadministration of CYP3A4 inducers, such as phenytoin, carbamazepine, and rifampin, can cause as much as a 50% reduction in levels of ketoconazole.
9.27 Pharmacokinetics
Oral absorption: Variable
Cmax 400 mg oral: c. 5–6 mg/L after 2 h
Plasma half-life: 6–10 h
Volume of distribution: 0.36 L/kg
Plasma protein binding: >95%
It is erratically absorbed after oral administration. Absorption is favored by an acid pH. Food delays absorption, but does not significantly reduce the peak serum concentration. Absorption is reduced if it is given with compounds that reduce gastric acid secretion. Penetration into CSF is generally poor and unreliable, although effective concentrations have been recorded with high doses in some cases of active meningitis. It is extensively metabolized by the liver, and the metabolites are excreted in the bile. Less than 1% of an oral dose is excreted unchanged in the urine.
9.28 Clinical Use
Ketoconazole remains useful in the treatment of cutaneous and mucous membrane dermatophyte and yeast infections, but it has been replaced by the newer triazoles in the treatment of most serious Candida infections and disseminated mycoses. Ketoconazole is usually effective in the treatment of thrush, but fluconazole is superior to ketoconazole for refractory thrush. Widespread dermatophyte infections on skin surfaces can be treated easily with oral ketoconazole when the use of topical antifungal agents would be impractical. Treatment of vulvovaginal candidiasis with topical imidazoles is less expensive.
9.29 Side effects
Nausea, vomiting, and anorexia occur commonly with ketoconazole, especially when high doses are prescribed. Epigastric distress can be reduced by taking ketoconazole with food. Pruritis and/or allergic dermatitis occurs in 10% of patients. Liver enzyme elevations during therapy are not unusual and are usually reversible. Severe ketoconazole-associated hepatitis is rare.
At high doses, ketoconazole causes a clinically significant reduction in testosterone synthesis and blocks the adrenal response to corticotropin. Gynecomastia, impotence, reduced sperm counts, and diminished libido can occur in men, and prolonged drug use can result in irregular menses in women. These hormonal effects have led to the use of ketoconazole as a potential adjunctive treatment for prostatic carcinoma.
9.30 Synthesis
Ketoconazole, cis-1-acetyl-4-[4-[2-(2,4-dichlorophenyl)-2-(1H-imidazole- 1-ylmethyl)-1,3-dioxolan-4-ylmethyl]phenyl]piperazine (35.2.4), is synthesized from 2,4-dichlorophenacyl bromide, the ketalization of which using glycerol gives cis-2-(2,4- dichlorophenyl)-2-bromoethyl-4-hydroxymethyl-1,3-dioxolane (35.2.1). Acylating the hydroxyl group of this compound with benzoyl chloride, and then alkylating the resulting compound with imidazole gives the derivative (35.2.2). Next, alkaline hydrolysis removes the benzoyl group, and a reaction with methanesulfonyl chloride gives a mesylate (35.2.3). Finally, alkylating the resulting 1-acetyl-4-(4-hydroxyphenyl)piperazine gives ketoconazole (35.2.4).

9.31 Storage Conditions
(0.4 mmol) was added to an oven-dried 15 mL sealed tube equipped with a magnetic stir bar with a magnetic stirrer.Sulfur powder (S8) (0.8 mmol), ethyl bromodifluoroacetate (1.0 mmol) in sodium hydroxymethanesulfinate (HOCH2SO2Na) (0.8 mmol) as a solventThe reaction was stirred at 100 C for 24 hours in a solution of N, N-dimethylacetamide (DMA) (2.0 mL).After the reaction is completed, the reaction mixture is cooled to room temperature. The mixture is saturated with brine and ethyl acetate.Ester solvent extraction, The combined organic layers were dried over anhydrous Na 2SO Flash column chromatography was performed using 300-400 mesh silica gel, and the crude mixture was purified by preparative TLC monitoring spotting.The product (I-32) was obtained as a yellow oil, yield 43%.Adding
9.32 Veterinary Drugs and Treatments
Because of its comparative lack of toxicity when compared to amphotericin B, oral administration, and relatively good efficacy, ketoconazole has been used to treat several fungal infections in dogs, cats, and other small species. Ketoconazole is often employed with amphotericin B to enhance the efficacy of ketoconazole, and by reducing the dose of amphotericin B, decreasing its risk of toxicity. See the Dosage section or Pharmacology section for specifics. Newer antifungal agents (fluconazole, itraconazole) have advantages over ketoconazole, primarily less toxicity and/or enhanced efficacy; however, ketoconazole can be significantly less expensive than the newer agents. Ketoconazole is considered by some to still be the drug of choice for treating histoplasmosis in dogs.
Use of ketoconazole in cats is controversial and some say it should never be used that species. Ketoconazole is also used clinically for the medical treatment of hyperadrenocorticism in dogs. Ketoconazole appears to be a viable option (although relatively expensive) to mitotane, particularly for palliative therapy in dogs with large, malignant, or invasive tumors where surgery is not an option. Ketoconazole is also used frequently in dogs for stabilization prior to surgery. It is a reversible inhibitor of steroidogenesis, so it is usually not a viable option for long-term treatment.
Because it interferes with the metabolism of cyclosporine, it has been used to reduce the dosage necessary for cyclosporine in dogs.
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9.33 Drug interactions
Potentially hazardous interactions with other drugs Aminophylline and theophylline; possibly increased concentration of aminophylline and theophylline. Analgesics: inhibits buprenorphine metabolism - reduce buprenorphine dose; possible increased risk of ventricular arrhythmias with methadone - avoid; increases oxycodone and sufentanil concentration; avoid with paracetamol. Anti-arrhythmics: increased risk of ventricular arrhythmias with disopyramide - avoid; concentration of dronedarone increased - avoid. Antibacterials: metabolism increased by rifampicin; may reduce rifampicin concentration; concentration of bedaquiline increased - avoid; avoid with fidaxomicin; concentration possibly reduced by isoniazid; avoid with clarithromycin and telithromycin in severe renal (both) and hepatic impairment (telithromycin only). Anticoagulants: anticoagulant effect of coumarins enhanced; concentration of apixaban, dabigatran and rivaroxaban increased - avoid; concentration of edoxaban increased - reduce edoxaban dose. Antidepressants: avoid concomitant use with reboxetine; ketoconazole increases concentration of mirtazapine. Antidiabetics: concentration of pioglitazone, saxagliptin and tolbutamide increased. Antiepileptics: concentration of ketoconazole reduced by fosphenytoin and phenytoin and possibly carbamazepine; concentration of perampanel and possibly carbamazepine increased. Antifungals: concentration of isavuconazole increased - avoid. Antihistamines: concentration of loratidine possibly increased - avoid; avoid with mizolastine; concentration of rupatadine increased. Antimalarials: avoid with piperaquine with artenimol and artemether and lumefantrine; concentration of mefloquine increased. Antimuscarinics: absorption of ketoconazole reduced; concentration of darifenacin increased - avoid; reduce dose of fesoterodine; concentration of oxybutynin and solifenacin increased; avoid with tolterodine. Antipsychotics: increased risk of ventricular arrhythmias with pimozide - avoid; possibly increased concentration of quetiapine - reduce quetiapine dose; inhibits aripiprazole metabolism - reduce aripiprazole dose; concentration of lurasidone increased - avoid
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9.34 Metabolism
Ketoconazole is extensively degraded by the liver, and very little active drug is excreted in either the urine or bile; the dose need not be modified for renal insufficiency. Adverse reactions to topical ketoconazole are very rare.
9.35 Precautions
Both rifampin and isoniazid lower plasma ketoconazolelevels, and concomitant administration should be avoided.Phenytoin serum levels should be monitored closelywhen ketoconazole is prescribed.Ketoconazole causes increasesin serum concentrations of warfarin, cyclosporine,and sulfonylureas. Because of its ability to increase serumcyclosporine levels, ketoconazole has been given to cyclosporine-dependent cardiac transplant recipients to reducethe dose of cyclosporine needed and as a cost-savingmeasure.
9.36 References
1) Lambert et al. (1986) The effects if ketoconazole on adrenal and testicular steroidogenesis in vitro; Biochem. Pharmacol. 35 3999
2) Sai et al. (2000) Assessment of specificity of eight chemical inhibitors using cDNA-expressed cytochromes P450. Xenobiotica 30 327
3) Loose et al. (1983) Ketoconazole blocks adrenal steroidogenesis by inhibiting cytochrome P450-dependent enzymes; J. Clin. Invest. 71 1495
4) Howell et al. (2019) Lung cancer cells survive epidermal growth factor receptor tyrosine kinase inhibitor exposure through upregulation of cholesterol synthesis; FASEB Bioadv. 2 90
5) Beetens et al. (1986) Ketoconazole inhibits the biosynthesis of leukotrienes in vitro and in vivo; Biochem. Pharmacol. 35 883
9.37 Usage
Ketoconazole is used to treat candidiasis, chronic mucocutaneous candidiasis, oral thrush, candiduria, blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. Ketoconazole is an antifungal agent.
9.38 Merck
10. Computational chemical data
  • Molecular Weight: 534.452g/mol
  • Molecular Formula: C26H28Cl2N4O4
  • Compound Is Canonicalized: True
  • XLogP3-AA: null
  • Exact Mass: 530.1487608
  • Monoisotopic Mass: 530.1487608
  • Complexity: 735
  • Rotatable Bond Count: 7
  • Hydrogen Bond Donor Count: 0
  • Hydrogen Bond Acceptor Count: 6
  • Topological Polar Surface Area: 69.1
  • Heavy Atom Count: 36
  • Defined Atom Stereocenter Count: 2
  • Undefined Atom Stereocenter Count: 0
  • Defined Bond Stereocenter Count: 0
  • Undefined Bond Stereocenter Count: 0
  • Isotope Atom Count: 0
  • Covalently-Bonded Unit Count: 1
11. Question & Answer
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