ChemicalBook > Product Catalog > API > Synthetic Anti-infective Drugs > Antifungal Drugs > Ketoconazole
Basic information Antifungal drug Pharmacological effects Pharmacokinetics Indications Side effects Precautions Pregnant and lactating women Chemical Properties Uses Production method Category Toxicity grading Acute toxicity Flammability and hazardous characteristics Storage characteristics Extinguishing agent Safety Related Supplier
Ketoconazole Chemical Properties
- Melting point:146°C
- Boiling point:753.4±60.0 °C(Predicted)
- Density 1.4046 (rough estimate)
- refractive index -10.5 ° (C=0.4, CHCl3)
- Flash point:9℃
- storage temp. 2-8°C
- solubility methanol: soluble50mg/mL
- pkapKa 3.25/6.22(H2O,t =25,I=0.025) (Uncertain)
- form Off-white solid
- color white to light yellow
- optical activity[α]20/D -1 to 1°, c = 4 in methanol
- Water Solubility Soluble in DMSO, ethanol, chloroform, water, and methanol.
- Merck 14,5302
- CAS DataBase Reference65277-42-1(CAS DataBase Reference)
- Hazard Codes T,N,F
- Risk Statements 25-36/37/38-23/24/25-50/53-48/22-60-39/23/24/25-11
- Safety Statements 36-45-36/37/39-26-61-60-53-36/37-16-7
- RIDADR UN 2811 6.1/PG 3
- WGK Germany 3
- RTECS TK7912300
- HazardClass 6.1(b)
- PackingGroup III
- HS Code 29349990
- Hazardous Substances Data65277-42-1(Hazardous Substances Data)
- ToxicityLD50 in mice, rats, guinea pigs, dogs (mg/kg): 44, 86, 28, 49 i.v.; 702, 227, 202, 780 orally (Heel)
Ketoconazole Usage And Synthesis
- Antifungal drugKetoconazole 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.
- Pharmacological effects1. 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.
- PharmacokineticsThis 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.
- IndicationsKetoconazole 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.
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.
The above information is edited by the chemicalbook of Dai Xiongfeng.
- Side effectsExternal 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.
- Precautions1. 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.
- Pregnant and lactating womenThe 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.
- Chemical PropertiesIt is white crystalline powder with the melting point being 146 ℃ and insoluble in water.
- UsesIt is antifungal drug for being used to treat athlete's foot and excessive dandruff.
- Production methodPut 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.
- CategoryToxic substances
- Toxicity gradingHighly toxic
- Acute toxicityOral-rat LD50: 166 mg/kg; Oral-Mouse LD50: 618 mg/kg.
- Flammability and hazardous characteristicsIt is combustible with burning releasing toxic chloride fumes and nitrogen oxides.
- Storage characteristicsTreasury: ventilation, low-temperature and dry; store it separately from food raw materials.
- Extinguishing agentDry powder, foam, sand, carbon dioxide, water mist.
- Chemical PropertiesWhite or almost white powder.
- Usesantifungal, PXR/SRC1 & CAR/SRC1 inhibitor
- UsesFor the treatment of the following systemic fungal infections: candidiasis, chronic mucocutaneous candidiasis, oral thrush, candiduria, blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis.
- UsesAn inhibitor of CYP proteins, thromboxane synthetase, and 5-LO
- UsesInhibits 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
- IndicationsKetoconazole (Nizoral) is approved for treating dermatophyte infections unresponsive to griseofulvin and for patients unable to tolerate that drug. A single oral dose is also effective for the treatment of pityriasis versicolor. Other effective drugs that are less hepatotoxic may be preferred, however.
- IndicationsKetoconazole (Nizoral) 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.
- IndicationsKetoconazole (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.
- Manufacturing Process(A) A mixture of 33.8 parts of 4-(4-piperazinyl)phenol dihydrobromide, 11.2
parts of acetic acid anhydride, 42 parts of potassium carbonate and 300 partsof 1,4-dioxane is stirred and refluxed for 3 days. The reaction mixture is
filtered and the filtrate is evaporated. The solid residue is stirred in water and
sodium hydrogen carbonate is added. The whole is stirred for 30 minutes. The
precipitated product is filtered off and dissolved in a diluted hydrochloric acid
solution. The solution is extracted with trichloromethane. The acid aqueous
phase is separated and neutralized with ammonium hydroxide. The product is
filtered off and crystallized from ethanol, yielding 5.7 parts of 1-acetyl-4-(4-
hydroxyphenyl)piperazine; MP 181-183°C.
(B) A mixture of 2.4 parts of 1-acetyl-4-(4-hydroxyphenyl)piperazine, 0.4 part of sodium hydride dispersion 78%; 75 parts of dimethylsulfoxide and 22.5 parts of benzene is stirred for one hour at 40°C. Then there are added 4.2 parts of cis-2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4- ylmethyl methane sulfonate and stirring is continued overnight at 100°C. The reaction mixture is cooled and diluted with water. The product is extracted with 1,1'-oxybisethane. The extract is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 3.2 parts (59%) of cis-1-acetyl-4-[2-(2,4-dichlorophenyl)- 2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-ylmethoxyl phenyl]piperazine; MP 146°C.
- brand nameKetozole (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.
- Therapeutic FunctionAntifungal
- 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.
- Antimicrobial activityThe spectrum includes dermatophytes, some dimorphic fungi and Candida spp.
- Acquired resistanceResistance 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.
- Pharmaceutical ApplicationsA synthetic dioxolane imidazole available for oral and topical use.
- Biological ActivityAntifungal agent; potent inhibitor of cytochrome P450c17.
- 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.
- PharmacokineticsOral 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.
- Clinical UseMucosal candidosis
Non-life-threatening forms of blastomycosis, coccidioidomycosis, histoplasmosis and paracoccidioidomycosis
- Clinical UseKetoconazole 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.
- Clinical UseKetoconazole can be used as palliative treatment for Cushing’s syndrome in patients undergoing surgery or receiving pituitary radiation and in those for whom more definitive treatment is still contemplated. Because surgical treatment is not always well tolerated by elderly patients, ketoconazole 200 to 1,000 mg/day can be a valuable alternative for the control of hypercortisolism. Common side effects include pruritus, liver dysfunction, and gastrointestinal symptoms.
- Side effectsBecause of its effectiveness in blocking C17-20 lyase activities, ketoconazole does not enhance existing hirsutism associated with metyrapone. On the other hand, the antiandrogenic effects of ketoconazole may prove disconcerting to male patients.
- Side effectsNausea, 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.
- Side effectsUnwanted effects include nausea, vomiting, abdominal pain, headache, rashes, urticaria and pruritus. Transient abnormalities of liver enzymes, interference with testosterone synthesis (leading to gynecomastia, alopecia and oligospermia) and rare fatal hepatic damage have been reported.
- Veterinary Drugs and TreatmentsBecause 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.
- MetabolismKetoconazole 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.
- PrecautionsBoth 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.
Ketoconazole Preparation Products And Raw materials
- Ketoconazole(Nizoral) (2S-CIS)-2-(2,4-DICHLOROPHENYL)-2-(1H-IMIDAZOL-1-YLMETHYL)-1,3-DIOXOLANE-4-METHANOL, METHANESULFONATE (ESTER)KETOCONAZOLE Ketoconazole USP 224-trichloroacetophenone (intermediate of ketoconazole) ketoconazole oleate Ketoconazole USP/CP2000/EP2002 KETOCONAZOLE, [ACETYL-1-14C] KETOCONAZOLE-D8 Ketoconazole Dichlorophenyl Acetylacetone Acetyl coenzyme A sodium salt 1,4-Dioxane Selenium dioxide Acetyl chloride Dichlorodiphenylsilane ACETYLACETONATE tributyl acetocitrate
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