Molecule

Drug Groups

approved; investigational

Description

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]

Indication

For the treatment of the following fungal infections in immunocompromised and non-immunocompromised patients: pulmonary and extrapulmonary blastomycosis, histoplasmosis, aspergillosis, and onychomycosis.

Pharmacology

Itraconazole is an imidazole/triazole type antifungal agent. Itraconazole is a highly selective inhibitor of fungal cytochrome P-450 sterol C-14 α-demethylation via the inhibition of the enzyme cytochrome P450 14α-demethylase. This enzyme converts lanosterol to ergosterol, and is required in fungal cell wall synthesis. The subsequent loss of normal sterols correlates with the accumulation of 14 α-methyl sterols in fungi and may be partly responsible for the fungistatic activity of fluconazole. Mammalian cell demethylation is much less sensitive to fluconazole inhibition. Itraconazole exhibits in vitro activity against Cryptococcus neoformans and Candida spp. Fungistatic activity has also been demonstrated in normal and immunocompromised animal models for systemic and intracranial fungal infections due to Cryptococcus neoformans and for systemic infections due to Candida albicans.

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.

Affected Organisms

Biotransformation

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.

Absorption

The absolute oral bioavailability of itraconazole is 55%, and is maximal when taken with a full meal.

Half Life

21 hours

Protein Binding

99.8%

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.

Distribution

* 796 ± 185 L

Clearance

* 381 +/- 95 mL/minute [IV administration]

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