Sporal Mechanism of Action

Sporal is the first orally active broad-spectrum triazole antifungal.
Pharmacology: In vitro studies have demonstrated that Sporal interferes with the heme-iron and apoprotein-binding activity of the fungal cytochrome P-450. This blocks the normal action of the enzymes and prevents the demethylation reaction which is necessary for the biosynthesis of ergosterol. Activity of membrane-bound enzymes decrease and uncoordinate synthesis of chitin. These abnormalities are toxic to fungal cell.
Pharmacokinetics: The oral bioavailability of Sporal is maximal when the capsules are given 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 Sporal 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 Sporal is 99.8%. Concentrations of Sporal 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 Sporal is related to epidermal regeneration. Therefore, therapeutic levels in the skin persist for 2-4 weeks after discontinuation of a 4-week treatment.
Sporal is also present in sebum and to a lesser extent in sweat. Sporal is also extensively distributed into tissues which 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 twice daily.
Sporal is extensively metabolized by the liver into a large number of metabolites. One of the metabolites is hydroxy-itraconazole, which has in vitro a comparable antifungal activity to Sporal. Antifungal drug levels measured by bioassay were about 3 times those of Sporal 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 a dose is excreted as metabolites in the urine within 1 week.
Microbiology: Sporal is active against infections with dermatophytes (Trichophyton and Microsporum sp, Epidermophyton floccosum), yeasts (Candida and Pityrosporum sp), Aspergillus sp and various other yeasts and fungi.