| Identification | More | [Name]
Ketoconazole | [CAS]
65277-42-1 | [Synonyms]
(+/-)-CIS-1-ACETYL-4-(4-[(2-[2,4-DICHLOROPHENYL]-2-[1H-IMIDAZOL-1-YLMETHYL]-1,3-DIOXOLAN-4-YL)-METHOXY]PHENYL)PIPERAZINE
[+/-]-CIS-1-ACETYL-4-[4-([2-(2,4-DICHLOROPHENYL)-2-(1H-IMIDAZOL-1-YLMETHYL)-1,3-DIOXOLAN-4-YL]-METHOXY)-PHENYL]PIPERAZINE
CIS-1-ACETYL-4-[4-[[2-(2,4-DICHLOROPHENYL)-2-(1H-IMIDAZOL-1-YLMETHYL)-1,3-DIOXOLAN-4-YL]METHOXY]PHENYL]PIPERAZINE
KETOCANAZOLE
KETOCONAZOLE
KETOCONAZOLE-D3
R-41400
,3-dioxolan-4-yl)methoxy)phenyl)-,cis-
fungarest
fungoral
ketoconazol
ketoderm
ketoisdin
kw-1414
nizoral
orifungalm
panfungol
piperazine,1-acetyl-4-(4-((2-(2,4-dichlorophenyl)-2-(1h-imidazol-1-ylmethyl)-1
KETOKONAZOL
Ketoconazole USP25/EP2002/CP2000 | [EINECS(EC#)]
265-667-4 | [Molecular Formula]
C26H28Cl2N4O4 | [MDL Number]
MFCD00058579 | [Molecular Weight]
531.43 | [MOL File]
65277-42-1.mol |
| Chemical Properties | Back Directory | [Appearance]
White Powder | [Melting point ]
148-152 °C | [Boiling point ]
753.4±60.0 °C(Predicted) | [density ]
1.4046 (rough estimate) | [refractive index ]
-10.5 ° (C=0.4, CHCl3) | [Fp ]
9℃ | [storage temp. ]
2-8°C
| [solubility ]
methanol: soluble50mg/mL | [form ]
Off-white solid | [pka]
pKa 3.25/6.22(H2O,t =25,I=0.025) (Uncertain) | [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. | [Usage]
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 | [Merck ]
5302 | [BCS Class]
2 | [Stability:]
Stable for 2 years from date of purchase as supplied. Solutions in DMSO or ethanol may be stored at -20°C for up to 3 months. | [InChIKey]
XMAYWYJOQHXEEK-OZXSUGGESA-N | [LogP]
4.350 | [CAS DataBase Reference]
65277-42-1(CAS DataBase Reference) |
| Safety Data | Back Directory | [Hazard Codes ]
T | [Risk Statements ]
R25:Toxic if swallowed.
R36/37/38:Irritating to eyes, respiratory system and skin .
R23/24/25:Toxic by inhalation, in contact with skin and if swallowed . | [Safety Statements ]
S36:Wear suitable protective clothing .
S45:In case of accident or if you feel unwell, seek medical advice immediately (show label where possible) .
S36/37/39:Wear suitable protective clothing, gloves and eye/face protection .
S26:In case of contact with eyes, rinse immediately with plenty of water and seek medical advice . | [RIDADR ]
UN 2811 6.1/PG 3
| [WGK Germany ]
3
| [RTECS ]
TK7912300
| [HazardClass ]
6.1(b) | [PackingGroup ]
III | [HS Code ]
29349900 | [Hazardous Substances Data]
65277-42-1(Hazardous Substances Data) | [Toxicity]
LD50 in mice, rats, guinea pigs, dogs (mg/kg): 44, 86, 28, 49 i.v.; 702, 227, 202, 780 orally (Heel) |
| Hazard Information | Back Directory | [Description]
Ketoconazole (65277-42-1) is?a broad spectrum antifungal agent which acts via inhibition of a cytochrome P450, CYP51A1 which is a lanosterol 14α-demethylase.1 Also inhibits CYP3A and CYP1A1.2 Inhibits adrenal steroidogenesis.3 Downregulates cholesterol synthesis in drug-tolerant human lung cancer cell lines.4 Blocks the biosynthesis of leukotrienes (LT) via inhibition of 5-lipoxygenase and dose dependently inhibits LT-mediated bronchoconstriction in guinea pigs.5 | [Originator]
Nizoral,Janssen,US,1981 | [Definition]
ChEBI: (2R,4S)-ketoconazole is a cis-1-acetyl-4-(4-{[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazine which dioxolane moiety has (2R,4S)-configuration. It is an enantiomer of a (2S,4R)-ketoconazole. | [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 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. | [Therapeutic Function]
Antifungal | [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 activity]
The spectrum includes dermatophytes, some dimorphic fungi
and Candida spp. | [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. | [General Description]
Pharmaceutical secondary standards for application in quality control, provide pharma laboratories and manufacturers with a convenient and cost-effective alternative to the preparation of in-house working standards.
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. | [Pharmaceutical Applications]
A synthetic dioxolane imidazole available for oral and topical
use. | [Biological Activity]
Antifungal agent; potent inhibitor of cytochrome P450c17. | [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. | [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. | [Clinical Use]
Ketoconazole 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. | [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. | [Clinical Use]
Mucosal candidosis
Pityriasis versicolor
Seborrheic dermatitis
Non-life-threatening forms of blastomycosis, coccidioidomycosis,
histoplasmosis and paracoccidioidomycosis | [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).
| [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. | [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 | [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. | [storage]
Desiccate at +4°C | [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 |
| Questions And Answer | Back Directory | [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.
| [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.
| [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.
| [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.
The above information is edited by the chemicalbook of Dai Xiongfeng. | [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.
| [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.
| [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.
| [Chemical Properties]
It is white crystalline powder with the melting point being 146 ℃ and insoluble in water.
| [Uses]
It is antifungal drug for being used to treat athlete's foot and excessive dandruff.
| [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.
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