| Indication |
For the treatment of the following fungal infections in
immunocompromised and non-immunocompromised patients: pulmonary and
extrapulmonary blastomycosis, histoplasmosis, aspergillosis, and
onychomycosis. |
| Pharmacodynamics |
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. |
| Mechanism of action |
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. |
| Absorption |
The absolute oral bioavailability of itraconazole is 55%, and is maximal when taken with a full meal. |
| Volume of distribution |
|
| Protein binding |
99.8% |
| 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 |
| Clearance |
- 381 +/- 95 mL/minute [IV administration]
|
| 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. |
