Itraconazole is a synthetic broad-spectrum antifungal agent.
In vitro studies have demonstrated that itraconazole impairs the synthesis of ergosterol in fungal cells. Ergosterol is a vital cell membrane component in fungi. Impairment of its synthesis ultimately results in an antifungal effect.
Microbiology: Itraconazole, a triazole derivative, is active against infections with dermatophytes (Trichophyton and Microsporum spp, Epidermophyton floccosum), yeasts (Cryptococcus neoformans, Pityrosporum and Candida spp, including C. albicans, C. glabrata and C. krusei), Aspergillus and Histoplasma spp, Paracoccidioides brasiliensis, Sporothrix schenckii, Fonsecaea and Cladosporium spp, Blastomyces dermatitidis, and various other yeasts and fungi.
Pharmacokinetics: The oral bioavailability of itraconazole is maximal when the capsules are taken immediately after a full meal. Peak plasma levels are reached 3-4 hrs following an oral dose. Elimination from plasma is biphasic with a terminal half-life of 1-1.5 days. During chronic administration, steady-state is reached after 1-2 weeks. Steady-state plasma concentrations of itraconazole 3-4 hrs after drug intake are 0.4 mcg/mL (100 mg once daily), 1.1 mcg/mL (200 mg once daily) and 2 mcg/mL (200 mg twice daily).
The plasma protein-binding of itraconazole is 99.8%. Concentrations of itraconazole in whole blood are 60% of those in plasma. Uptake in keratinous tissues, especially the skin, is up to 4 times higher than in plasma, and elimination of itraconazole is related to epidermal regeneration. In contrast to the plasma levels which become undetectable within 7 days of stopping therapy, therapeutic levels in the skin persist for 2-4 weeks after discontinuation of a 4-week treatment. Levels of itraconazole have been detected in the nail keratin as early as 1 week after start of treatment and persist for at least 6 months after the end of a 3-month course of therapy. Itraconazole is also present in sebum and to a lesser extent in sweat.
Itraconazole is also extensively distributed into tissues that are prone to fungal invasion. Concentrations in lung, kidney, liver, bone, stomach, spleen and muscle were found to be 2-3 times higher than the corresponding plasma concentration.
Therapeutic levels in vaginal tissue are maintained for another 2 days after discontinuation of a 3-day course with 200 mg daily and for another 3 days after discontinuation of a 1-day course with 200 mg 2 times a day.
Itraconazole is extensively metabolized by the liver into a large number of metabolites. One of the metabolites is hydroxy-itraconazole, which has a comparable antifungal activity in vitro to itraconazole. Antifungal drug levels measured by bioassay were about 3 times those of itraconazole assayed by high-performance liquid chromatography. Faecal excretion of the parent drug varies between 3-18% of the dose. Renal excretion of the parent drug is <0.03% of the dose. About 35% of the dose is excreted as metabolites in the urine within 1 week.