What Is Ketoconazole?

Ketoconazole is an off-white crystalline powder; it is odorless and tasteless. This product is easily soluble in chloroform, soluble in methanol, slightly soluble in ethanol, and almost insoluble in water. Melting point The melting point of this product is 146 ° C. The specific rotation is taken from this product and accurately weighed. Methanol is added to make a solution containing 40 mg per 1ml. It is measured according to the law. The calculated specific rotation is -1 ° to + 1 °. The product is a pink suspension.

Chinese name: Ketoconazole

Chinese alias: ketoconazide; ketoconazole; cis-1-acetyl-4- [4-[[2- (2,4-dichlorophenyl) -2- (1H-imidazol-1-yl (Methyl) -1,3-dioxolane-4-yl] methoxy] phenyl] piperazine (system name); Conte; Rislau; Enzyme Kangling; Nizolar; Ketoimidazole

English name: Ketoconazole

English alias: fungoral; Onofin K; nizoral; ketoderm; fungarest; 1- [4- (4 [(2 R , 4 S ) -2- (2,4-Dichlorophenyl) -2- (1 H -imidazol-1- ylmethyl) -1,3-dioxolan-4-yl] methoxy} phenyl) piperazin-1-yl] ethan-1-one

CAS number: 65277-42-1

EINECS: 265-667-4

Molecular formula: C ₂₆ H ₂₈ Cl ₂ N ₄ O ₄

Appearance and properties: white to off-white crystalline powder

Density: 1.38g / cm ³

Melting point: 146 ° C

Boiling point: 753.4ºC at 760 mmHg

Flash point: 409.4ºC

Refractive index: -10.5 ° (C = 0.4, CHCl3)

Stability: Stable at room temperature in a closed container under normal storage and operating conditions

Storage conditions: The storeroom is ventilated, low-temperature and dry, and stored separately from food ingredients

Symbol: GHS06 GHS08 GHS09

Signal Word: Danger

Hazard statement: H301; H360F; H373; H410

Cautionary statements: P201; P273; P301 + P310; P308 + P313; P501

Packing level: III

Hazard category: 6.1 (b)

Customs code: 2933990090

Dangerous Goods Transport Code: UN 2811 6.1 / PG 3

WGK Germany: 3

Danger category code: R25

Safety instructions: S36-S45

RTECS number: TK7912300

Dangerous goods mark: T ^[1]

CAS number: 65277-42-1

MDL number: MFCD00058579

EINECS number: 265-667-4

RTECS number: TK7912300

PubChem number: 24278176 ^[2]

Properties: White crystalline powder.

Density (g / mL, 25/4 ): 1.38

Relative vapor density (g / mL, air = 1): Not determined

Melting point (ºC): 146

Boiling point (ºC, normal pressure): 753.4

Boiling point (ºC, 5.2kPa): Not determined

Refractive index: Not determined

Flash point (ºC): Not determined

Specific rotation (º): Not determined

Auto-ignition point or ignition temperature (ºC): Not determined

Vapor pressure (kPa, 25ºC): Not determined

Saturated vapor pressure (kPa, 60ºC): Not determined

Combustion heat (KJ / mol): 109.78

Critical temperature (ºC): Not determined

Critical pressure (KPa): Not determined

Logarithm of oil-water (octanol / water) partition coefficient: not determined

Upper explosion limit (%, V / V): Not determined

Lower explosion limit (%, V / V): Not determined

Solubility: Insoluble in water. ^[2]

Mouse, rat, guinea pig, dog LD50 (mg / kg): 44, 86, 28, 49 intravenous injection
702, 227, 202, 700 orally. ^[2]

It is generally not harmful to water. Do not discharge materials into the surrounding environment without government permission. ^[2]

Molar refractive index: 139.11

Molar volume (cm3 / mol): 384.9

Isometric Zhang Rong (90.2K): 1034.5

Surface tension (dyne / cm): 52.1

Polarizability (10-24cm3): 55.15 ^[2]

Hydrophobic parameter calculation reference value (XlogP): 4.3

Number of hydrogen-bonded donors: 0

Number of hydrogen bond acceptors: 8

Number of rotatable chemical bonds: 7

Topological molecular polar surface area (TPSA): 69.1

Number of heavy atoms: 36

Surface charge: 0

Complexity: 736

Number of isotope atoms: 0

Determine the number of atomic stereocenters: 2

Uncertain number of atomic stereocenters: 0

Determine the number of chemical bond stereocenters: 0

Uncertain number of chemical bond stereocenters: 0

Number of covalent bond units: 1 ^[2]

Keep away from oxides. ^[2]

Store in a sealed container in a cool, dry place. Store away from oxidizing agents. Store at 2-8 ºC. ^[2]

A mixture of 2.4 parts of 1-acetyl-4- (4-hydroxyphenyl) piperazine, 0.4 parts of 78% sodium hydride, 75 parts of dimethyl sulfate, and 22.5 parts of benzene was stirred at 40 ° C for 1 h, and then 4.2 parts of 2- (2,4-Dichlorobenzene-2- (1H-imidazol-1-ylmethyl) -1,3-dioxolane-4-ylmethyl methanesulfonate, stirred at 100 ° C overnight. The reaction formed Post-processing to obtain 3.2 parts of ketoconazole ^[1]

Ketoconazole is an imidazole antifungal drug. Its mechanism of action is to inhibit the biosynthesis of ergosterol on the cell membrane of fungi, affect the permeability of the cell membrane, and inhibit its growth. Ketoconazole can be used to treat superficial and deep mycosis, such as skin and nail itch, vaginal candidiasis, gastrointestinal fungal infections, etc. Infection ^[1]

Ketoconazole pharmacological effects

This product is an imidazole antifungal. It has bacteriostatic and bactericidal effects on skin fungi, yeasts (Candida, Pseudospora, Pseudococcus, Cryptococcus), biphasic fungi, and fungi. In addition to the fungi, this product The effects of mold, Mycosporium sporogenes, some dark-sporaceae, Mucor spp. Are weak. The mechanism of action of this product is mainly to highly selectively interfere with the activity of fungal cytochrome P-450, thereby inhibiting the biosynthesis of ergosterol on the fungal cell membrane.

Ketoconazole pharmacokinetics

This product dissolves in gastric acid and is easy to absorb. When gastric acid and acidity decrease, absorption can be reduced. It is widely distributed in the body after absorption, and can reach inflammatory synovial fluid, saliva, bile, urine, milk, tendons, skin and soft tissues, and feces. It has poor penetration to the blood-cerebrospinal fluid barrier. In most cases, the drug concentration in the cerebrospinal fluid is lower than 1 mg / L. This product can cross the blood-placental barrier. The serum protein binding rate was above 90%. After a single oral administration of 200mg and 400mg of this product, the peak plasma concentration (Cmax) was 3.6mg / L ± 1.65mg / L and 6.5mg / L ± 1.44mg / L, respectively. Peak time (tmax) is 1 to 4 hours. The bioavailability of this product after taking a meal is about 75%. The blood elimination half-life (t1 / 2?) Is 6.5 to 9 hours. Some drugs are metabolized in the liver into several inactive metabolites. It is mainly excreted by bile, and excreted by the kidney only accounts for 13% of the administered amount, of which 2% to 4% are excreted from the urine in the original form.

Ketoconazole indications

Systemic fungal infections, such as systemic candidiasis,

Candida Paracoccidiosis, histoplasmosis, coccidiosis, and blastomycosis.

Skin, hair, and finger (toe) infections caused by dermatophytes and / or yeast Mucosal candidiasis, etc.), when the local treatment is ineffective or the drug cannot be used due to factors such as the site, area and depth of the infection, this product can be used for treatment.

Chronic, recurrent vaginal candidiasis that is not effective with topical treatment.

It is used to prevent and treat patients who are susceptible to fungal infections due to reduced immune function (hereditary and caused by diseases or drugs).

Ketoconazole usage dosage

Dosage for general infection: 200mg per day. Until the symptoms disappear and the microbial culture results are negative. Usual course of treatment: fungal stomatitis for 10 days; skin and hair fungal diseases for 1 to 2 months; aspergillosis and systemic candidiasis for 1 to 2 months; coccidioidosis and histoplasmosis 2 to 6 Months; coccidioidomycosis, onychomycosis, and chronic mucocutaneous candidiasis can last up to 6-12 months. When the effect is not good, it can be doubled, that is, 400mg per day. Day service: vaginal candidiasis: 400mg once, twice a day for 5 days. Children's dosage: 50mg daily for 1-4 years old; 100mg daily for 5-12 years old. Prostate cancer: 800-1200mg per day ^[4] .

Ketoconazole drug interactions

This product is forbidden to be used in combination with astemizole, terfenadine and cisapride. Due to inhibition of cytochrome P-450 metabolism, the concentration of astemizole, terfenadine, or cisapride may increase, which may lead to heart rhythm disturbance and even death.

When combined with alcohol and hepatotoxic drugs, this product can increase the chance of liver toxicity. Patients receiving long-term treatment or pre-existing liver disease should be closely monitored when using these two drugs, and alcoholic beverages should be avoided.

Anticoagulants, warfarin coumarins, or indane dione derivatives can enhance the effect when combined with this product, leading to prolonged prothrombin time, so patients should be closely observed, the prothrombin time should be monitored, and the dose should be adjusted .

This product can increase the blood concentration of cyclosporine and may increase the risk of nephrotoxicity. Therefore, the combined application of these two drugs is only considered in the case of very close observation and monitoring of blood concentration. .

The combination of this product with antacids, anticholinergics, sedatives, histamine H2 receptor antagonists, omeprazole, sucralfate, etc. can significantly reduce the absorption of this product, so it should be avoided. If combined, take them at least 2 hours apart.

When this product is combined with rifampicin and isoniazid, the blood concentration decreases, which can lead to treatment failure or disease recurrence.

When phenytoin is combined with this product, the metabolism of phenytoin can be slowed, causing its blood concentration to be significantly increased, and the same fashion can be used to reduce the blood concentration of this product. Therefore, the response of the two types of drugs should be closely observed .

The buffering agent contained in didanosine (DDI) can increase the pH of the digestive tract, and the product is preferably absorbed in an acidic environment, so it can affect the absorption of the product when combined. Must be used at intervals of more than 2 hours.

This product has an antagonistic effect with amphotericin B, and the efficacy is weakened when used in combination.

Ketoconazole can affect budesonide's metabolism in vivo and has no significant clinical significance at the recommended dose.

Ketoconazole contraindications

Patients with acute and chronic liver disease, those with a history of liver disease, and those who are allergic to this product are prohibited.

Ketoconazole overdose

If overdose, sodium carbonate gastric lavage and supportive measures should be taken.

Ketoconazole adverse reactions

Hepatotoxicity: This product can cause elevated serum aminotransferases (AST, ALT), which is reversible. Occasionally severe hepatotoxicity is mainly hepatocellular type, with an incidence rate of about 0.01%. The clinical manifestations are jaundice, dark urine, white feces, and abnormal fatigue, which usually recover after stopping the drug, but there are also deaths; children There are also cases of hepatitis.

Gastrointestinal reactions: such as nausea, vomiting, and anorexia are more common.

When taken once a day at a dosage of 0.2g, a temporary decrease in plasma testosterone concentration may occur, and it usually returns to normal within 24 hours after taking the drug. For long-term treatment at this dose, the amount of testosterone was not significantly different from that of the control group.

The treatment dose exceeds 0.2g or 0.4g per day, and in rare cases, reversible male breast development and semen deficiency may occur.

Others: Drug rash, pruritus, dizziness, headache, abdominal pain, drowsiness, photophobia, paresthesia, leukocytes and thrombocytopenia, anemia, hair loss, allergic reactions, and transient elevated serum aminotransferases.

Ketoconazole precautions

Urticaria The following conditions should be used with caution: gastric acid deficiency (which may cause a significant reduction in the absorption of this product); alcoholism (this product can cause liver toxicity).

Liver function should be checked regularly before and during treatment. Elevated serum aminotransferase may not be accompanied by hepatitis symptoms, however, if the serum aminotransferase value continues to increase (even mildly) or exacerbates, or it is accompanied by symptoms of hepatotoxicity, the product should be discontinued immediately. treatment.

Due to the poor penetration of the blood-cerebrospinal fluid barrier, it is not suitable for the treatment of fungal meningitis.

Due to its poor antibacterial effect on Aspergillus, Mucor, or Mycobacterium pods, it is not recommended for the above fungal infections.

Interference with laboratory test indicators: Because this product can cause elevated serum aminotransferases, it can also cause increased blood bilirubin.

Women over 50 years have poor tolerance to this product.

Patients who have taken griseofulvin and concomitant medications that are harmful to the liver should pay attention to liver damage reactions, such as common burnout accompanied by fever and jaundice. For patients treated with griseofulvin, it is best to stop taking griseofulvin for one month before starting this product.

For healthy subjects taking a dose of more than 0.4g (including 0.4g) a day, it was found that this product can reduce the response of cortisone to corticotropin stimulation. Therefore, patients with adrenal insufficiency and prolonged stress (such as major surgery) should be monitored for adrenal function.

It is forbidden to take alcoholic beverages while taking the medicine. If dizziness and drowsiness occur, attention should be paid.

The product can be taken at the same time as food to promote the absorption of the product and reduce nausea and vomiting.

This product can cause photosensitivity, so you should avoid prolonged exposure to bright light during use, and you can wear colored glasses.

The course of treatment for candidiasis is at least 2 weeks, and the treatment should be continued until the pathogen examination infection disappears. Chronic cutaneous mucosal candidiasis often requires long-term maintenance treatment. The course of other systemic fungal infections takes 6 months or more.

When the product is used to treat patients with impaired renal function, it is generally not necessary to reduce the amount, because only a small amount of the drug is excreted from the kidney in the original form. Because this product can cause hepatotoxicity, patients with liver damage should not use this product. If there are indications, it should be used with caution and reduced dosage.

Because this product has a certain inhibitory effect on certain liver oxidases, it can delay the elimination of drugs that rely on this enzyme to metabolize, increase the blood drug concentration, and aggravate adverse reactions.

Occasionally, it is reported that the product has a drinking-like effect on drinkers, which manifests as flushing, rash, peripheral edema, nausea, and headache, which usually disappear within a few hours.

At the same time as cimetidine or furan Thiamine, the drug should be taken orally for at least 2 hours before taking the above drugs.

Medication for pregnant and lactating women

The product can be passed through the placenta, and animal experiments have confirmed that the product can be teratogenic, such as the occurrence of rat fingers (dose of 80mg / kg), little fingers (toes) and dystocia. According to the US FDA, the drug is classified as Class C in pregnant women, that is, it is toxic in animal experiments and lacks sufficient data for human studies. Therefore, pregnant women should still ban the product, although no problem has been confirmed in humans.

The product can be secreted into milk. The use of this product in humans has not been proven to be a problem, but since this product can increase the likelihood of nucleus jaundice in newborns, lactating women must weigh the pros and cons or suspend breastfeeding while taking this product.

Medication for children

The application of this product in children lacks systematic research data, and the application of children under 2 years old lacks data, so children under 2 years old are prohibited from using this product; children over 2 years old should be used with caution. If there are indications, they must weigh the advantages and disadvantages.