Ketoconazole
Synonym(s):(±)-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, R-41400, CYP17A1 Inhibitor I;Ketoconazole;Ketoconazole - CAS 65277-42-1 - Calbiochem
- CAS NO.:65277-42-1
- Empirical Formula: C26H28Cl2N4O4
- Molecular Weight: 531.43
- MDL number: MFCD00058579
- EINECS: 265-667-4
- SAFETY DATA SHEET (SDS)
- Update Date: 2024-05-22 17:52:39
What is Ketoconazole?
Absorption
Ketoconazole requires an acidic environment to become soluble in water. At pH values above 3 it becomes increasingly insoluble with about 10% entering solution in 1 h. At pH less than 3 dissolution is 85% complete in 5 min and entirely complete within 30 min. A single 200 mg oral dose produces a Cmax of 2.5-3 mcg/mL with a Tmax of 1-4 h. Administering ketoconazole with food consistently increases Cmax and delays Tmax but literature is contradictory regarding the effect on AUC, which may experience a small decrease. A bioavailablity of 76% has been reported for ketoconazole.
Toxicity
Symptoms of overdose include acute liver injury, which may include both hepatocellular and cholestatic injury, accompanied by anorexia, fatigue, nausea, and jaundice. In case of overdose, gastric lavage with activated charcoal may be used if within one hour of ketoconazole ingestion otherwise provide supportive care. If the patient shows signs of adrenal insufficiency, administer 100 mg hydrocortisone once together with saline and glucose infusion and monitor the patient closely. Blood pressure and fluid and electrolyte balance should be monitored over the next few days.
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.
The Uses of Ketoconazole
Ketoconazole is used to treat candidiasis, chronic mucocutaneous candidiasis, oral thrush, candiduria, blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis. Ketoconazole is an antifungal agent.
Indications
Ketoconazole is used to treat serious fungal or yeast infections, such as candidiasis (thrush, oral thrush), blastomycosis (Gilchrist's disease), coccidioidomycosis (Valley fever, San Joaquin Valley fever), histoplasmosis (Darling's disease), chromoblastomycosis (chromomycosis), or paracoccidioidomycosis (South American blastomycosis, Lutz-Splendore-Almeida disease). This medicine works by killing the fungus or yeast or preventing its growth.
Background
Ketoconazole is an imidazole antifungal agent used in the prevention and treatment of a variety of fungal infections. It functions by preventing the synthesis of ergosterol, the fungal equivalent of cholesterol, thereby increasing membrane fluidity and preventing growth of the fungus. Ketoconazole was first approved in an oral formulation for systemic use by the FDA in 1981. At this time it was considered a significant improvement over previous antifungals, miconazole and clotrimazole, due to its broad spectrum and good absorption. However, it was discovered that ketoconazole produces frequent gastrointestinal side effects and dose-related hepatitis. These effects combined with waning efficacy led to its eventual replacement by triazole agents, fluconazole, itraconazole, voriconazole, and posaconazole. Ketoconazole and its predecessor clotrimazole continue to be used in topical formulations.
What are the applications of Application
Ketoconazole is an inhibitor of CYP proteins, thromboxane synthetase, and 5-LO
Regulations
Due to its hepatotoxic side effects, oral ketoconazole was withdrawn from the European and Australian markets in 2013. The United States imposed strict relabeling requirements and restrictions for prescription, with Canada issuing a risk communication echoing these concerns. Today, oral ketoconazole is only indicated for endemic mycoses, where alternatives are not available or feasible. Meanwhile, topical ketoconazole is effective, safe, and widely prescribed for superficial mycoses, particularly as the first-line treatment for tinea versicolor.
Metabolism
The major metabolite of ketoconazole appears to be M2, an end product resulting from oxidation of the imidazole moiety. CYP3A4 is known to be the primary contributor to this reaction with some contribution from CYP2D6. Other metabolites resulting from CYP3A4 mediated oxidation of the imidazole moiety include M3, M4, and M5. Ketoconazole may also undergo N-deacetylation to M14, , alkyl oxidation to M7, N-oxidation to M13, or aromatic hydroxylation to M8, or hydroxylation to M9. M9 may further undergo oxidation of the hydroxyl to form M12, N-dealkylation to form M10 with a subsequent N-dealkylation to M15, or may form an iminium ion. No metabolites are known to be active however oxidation metabolites of M14 have been implicated in cytotoxicity.
Properties of Ketoconazole
Melting point: | 148-152 °C |
Boiling point: | 753.4±60.0 °C(Predicted) |
Density | 1.4046 (rough estimate) |
Flash point: | 9℃ |
storage temp. | 2-8°C |
solubility | methanol: soluble50mg/mL |
form | Off-white solid |
color | white to light yellow |
Water Solubility | Soluble in DMSO, ethanol, chloroform, water, and methanol. |
Safety information for Ketoconazole
Signal word | Danger |
Pictogram(s) |
Skull and Crossbones Acute Toxicity GHS06 Health Hazard GHS08 Environment GHS09 |
GHS Hazard Statements |
H301:Acute toxicity,oral H373:Specific target organ toxicity, repeated exposure H410:Hazardous to the aquatic environment, long-term hazard |
Precautionary Statement Codes |
P201:Obtain special instructions before use. P202:Do not handle until all safety precautions have been read and understood. P260:Do not breathe dust/fume/gas/mist/vapours/spray. P264:Wash hands thoroughly after handling. P264:Wash skin thouroughly after handling. P273:Avoid release to the environment. P301+P310:IF SWALLOWED: Immediately call a POISON CENTER or doctor/physician. |
Computed Descriptors for Ketoconazole
InChIKey | XMAYWYJOQHXEEK-OZXSUGGESA-N |
Abamectin manufacturer
Jigs Chemical ltd
PRODIGIOUS LIFE SCIENCES
STELLENCE PHARMSCIENCE PVT TLD
SNECOFRi PVT LTD
Shree HariKrishna Pharmaceuticals
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