Definition
Broad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients.
Ketoconazole (pronounced /ˌkiːtoʊˈkoʊnəzoʊl/) is a synthetic antifungal drug used to prevent and treat skin and fungal infections, especially in immunocompromised patients such as those with AIDS. Ketoconazole is sold commercially as an anti-dandruff shampoo. Ketoconazole is very lipophilic, which leads to accumulation in fatty tissues. The less toxic and more effective triazole compounds fluconazole and itraconazole have largely replaced ketoconazole for internal use. Ketoconazole is best absorbed at highly acidic levels, so antacids or other causes of decreased stomach acid levels will lower the drug's absorption when taken orally. -Wikipedia [HMDB]
Description
Ketoconazole is only found in individuals that have used or taken this drug. It is a broad spectrum antifungal agent used for long periods at high doses, especially in immunosuppressed patients. [PubChem]Ketoconazole interacts with 14-α demethylase, a cytochrome P-450 enzyme necessary for the conversion of lanosterol to ergosterol. This results in inhibition of ergosterol synthesis and increased fungal cellular permeability. Other mechanisms may involve the inhibition of endogenous respiration, interaction with membrane phospholipids, inhibition of yeast transformation to mycelial forms, inhibition of purine uptake, and impairment of triglyceride and/or phospholipid biosynthesis. Ketoconazole can also inhibit the synthesis of thromboxane and sterols such as aldosterone, cortisol, and testosterone.
Top Gene Interactions
Related Pathways
General Information
- Metabolism: Hepatic. Ketoconazole is partially metabolized in the liver to several inactive metabolites by oxidation and degradation of the imidazole and piperazine rings, by oxidative O-dealkylation, and by aromatic hydroxylation. (A625) Half Life: 2 hours
- Uses/Sources: Ketoconazole is an antifungal agent. It is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet, under the trademark name Nizoral by Johnson & Johnson. (L1908). It is used for the treatment of the following systemic fungal infections: candidiasis, chronic mucocutaneous candidiasis, oral thrush, candiduria, blastomycosis, coccidioidomycosis, histoplasmosis, chromomycosis, and paracoccidioidomycosis.
- Health Effects: Ketoconazole can cause liver problems. (L1536)
- Symptoms: Side effects of the potential hepatotoxicity of Ketoconazole include abdominal pain or tenderness, clay-colored stools, dark urine, decreased appetite, fever, headache, itching, loss of appetite, nausea and vomiting, skin rash, swelling of the feet or lower legs, unusual tiredness or weakness, and yellow eyes or skin. (L1536)
- Treatment: In the event of accidental overdosage, supportive measures, including gastric lavage with sodium bicarbonate, should be employed. (L1712)
- Route of Exposure: Oral (L1908) ; topical (L1908)
Toxicity
- Carcinogenicity: No indication of carcinogenicity to humans (not listed by IARC).
- Toxicity: Hepatotoxicity, LD<sub>50</sub>=86 mg/kg (orally in rat) LD50: 44 mg/kg (Intravenous, Mouse) (T66) LD50: 702 mg/kg (Oral, Mouse) (T66)
Mechanism of Action
| Target Name | Mechanism of Action | References |
|---|---|---|
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Aryl hydrocarbon receptor Potassium voltage-gated channel subfamily H member 2 Androgen receptor Cytochrome P450 3A4 Cytochrome P450 19A1 Multidrug resistance protein 1 25-hydroxyvitamin D-1 alpha hydroxylase, mitochondrial Vitamin D3 receptor Nuclear receptor subfamily 1 group I member 2 Sodium-dependent serotonin transporter Nuclear receptor subfamily 1 group I member 3 Bile salt export pump Nuclear receptor ROR-gamma Bile acid receptor NAD-dependent protein deacetylase sirtuin-2 Cytochrome P450 11B1, mitochondrial 17-hydroxylase Steroid 21-hydroxylase 11-hydroxylase Steroid 17-alpha-hydroxylase/17,20 lyase Sterol regulatory element-binding protein 1 Cytochrome P450 11B2, mitochondrial Malate dehydrogenase, cytoplasmic 1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial Sodium/bile acid cotransporter |
22079757 21384875 10820137 11751127 20594862 11063622 15828836 17291041 19049427 20684610 7473546 6304148 21058632 10565843 23611293 9526564 18061460 1526623 15272206 12699389 18672868 16570918 18674917 7608911 12477351 20550118 15615534 12739759 22444875 17145705 9379450 11262078 19211174 20869355 18763754 21129965 8863811 2004042 20413308 20568782 14521410 20655626 18672861 21341743 18939864 15743198 8765515 1495014 21174408 11716514 18778944 11087568 2231592 2966691 18024111 |
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| Lanosterol 14-alpha demethylase | Ketoconazole interacts with 14-α demethylase, a cytochrome P-450 enzyme necessary for the conversion of lanosterol to ergosterol. This results in inhibition of ergosterol synthesis and increased fungal cellular permeability. Other mechanisms may involve the inhibition of endogenous respiration, interaction with membrane phospholipids, inhibition of yeast transformation to mycelial forms, inhibition of purine uptake, and impairment of triglyceride and/or phospholipid biosynthesis. Ketoconazole can also inhibit the synthesis of thromboxane and sterols such as aldosterone, cortisol, and testosterone. (A365) |
11752352 17194716 8340925 17964172 19075057 |