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 |
14521410 20594862 11262078 18061460 22444875 17145705 15743198 20550118 12699389 18024111 19211174 2231592 8765515 15615534 11087568 18672868 15272206 1526623 21129965 19049427 10565843 18939864 20413308 21341743 18674917 18763754 1495014 21174408 8863811 12739759 10820137 20568782 20655626 18672861 2004042 20684610 7608911 23611293 6304148 16570918 21058632 20869355 11751127 9379450 15828836 18778944 22079757 12477351 21384875 11716514 9526564 2966691 7473546 11063622 17291041 |
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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 19075057 17964172 8340925 17194716 |