Definition
A triazole antifungal agent that inhibits cytochrome P-450-dependent enzymes required for ERGOSTEROL synthesis.
Description
Itraconazole is only found in individuals that have used or taken this drug. It is one of the triazole antifungal agents that inhibits cytochrome P-450-dependent enzymes resulting in impairment of ergosterol synthesis. It has been used against histoplasmosis, blastomycosis, cryptococcal meningitis & aspergillosis. [PubChem]Itraconazole interacts with 14-alpha demethylase, a cytochrome P-450 enzyme necessary to convert lanosterol to ergosterol. As ergosterol is an essential component of the fungal cell membrane, inhibition of its synthesis results in increased cellular permeability causing leakage of cellular contents. Itraconazole may also inhibit endogenous respiration, interact with membrane phospholipids, inhibit the transformation of yeasts to mycelial forms, inhibit purine uptake, and impair triglyceride and/or phospholipid biosynthesis.
Top Gene Interactions
Related Pathways
General Information
- Metabolism: Itraconazole is extensively metabolized by the liver into a large number of metabolites, including hydroxyitraconazole, the major metabolite. The main metabolic pathways are oxidative scission of the dioxolane ring, aliphatic oxidation at the 1-methylpropyl substituent, N-dealkylation of this 1-methylpropyl substituent, oxidative degradation of the piperazine ring and triazolone scission. Route of Elimination: Itraconazole is metabolized predominately by the cytochrome P450 3A4 isoenzyme system (CYP3A4) in the liver, resulting in the formation of several metabolites, including hydroxyitraconazole, the major metabolite. Fecal excretion of the parent drug varies between 3-18% of the dose. Renal excretion of the parent drug is less than 0.03% of the dose. About 40% of the dose is excreted as inactive metabolites in the urine. No single excreted metabolite represents more than 5% of a dose. Half Life: 21 hours
- Uses/Sources: For the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: pulmonary and extrapulmonary blastomycosis, histoplasmosis, aspergillosis, and onychomycosis.
- Route of Exposure: The absolute oral bioavailability of itraconazole is 55%, and is maximal when taken with a full meal.
Toxicity
- Carcinogenicity: No indication of carcinogenicity to humans (not listed by IARC).
- Toxicity: No significant lethality was observed when itraconazole was administered orally to mice and rats at dosage levels of 320 mg/kg or to dogs at 200 mg/kg.
- Lethal Dose: No significant lethality was observed when itraconazole was administered orally to mice and rats at dosage levels of 320 mg/kg or to dogs at 200 mg/kg. (A308)
Mechanism of Action
Target Name | Mechanism of Action | References |
---|---|---|
Multidrug resistance protein 1 Lanosterol 14-alpha demethylase |
Itraconazole interacts with 14-α demethylase, a cytochrome P-450 enzyme necessary to convert lanosterol to ergosterol. As ergosterol is an essential component of the fungal cell membrane, inhibition of its synthesis results in increased cellular permeability causing leakage of cellular contents. Itraconazole may also inhibit endogenous respiration, interact with membrane phospholipids, inhibit the transformation of yeasts to mycelial forms, inhibit purine uptake, and impair triglyceride and/or phospholipid biosynthesis. |
12621384 15969931 12699389 11752352 11808341 17194716 16041596 11716514 16084853 11751127 |
Cytochrome P450 3A4 C-X-C chemokine receptor type 1 Vasopressin V2 receptor C-C chemokine receptor type 4 |
12699389 18218784 23437772 |
Itraconazole Interacts with Diseases
Disease | Inference Score | References/Inference Genes |
Breast carcinoma | 17.96 |
|
Hepatocellular carcinoma | 17.25 |
|
Colorectal cancer | 15.09 |
|
Asthma | 14.12 |
|
Atopic eczema | 13.18 |
|
Arthritis, Experimental | 12.06 |
|
Prostatic Neoplasms | 11.27 |
|
Pulmonary Fibrosis | 11.26 |
|
Abortion, Spontaneous | 11.22 |
|
Cholestasis, progressive familial intrahepatic 1 | 10.59 |
|
Leishmaniasis, Cutaneous | 10.49 |
|
Intrahepatic Cholestasis of Pregnancy | 10.29 |
|
Hepatitis, Autoimmune | 10.25 |
|
Pancreatic carcinoma | 9.95 |
|
Hyperoxia | 9.72 |
|
Hepatitis, Alcoholic | 9.14 |
|
Primary biliary cirrhosis | 8.98 |
|
Rheumatoid arthritis | 8.81 |
|
Drug-induced liver injury | 8.59 |
|
Disease Progression | 8.45 |
|