Pharmacology: Mechanism of Action: Fungistatic; may be fungicidal, depending on concentration; azole antifungals interfere with cytochrome P450 enzyme activity, which is necessary for the demethylation of 14-alpha-methylsterols to ergosterol. Ergosterol, the principal sterol in the fungal cell membrane, becomes depleted. This damages the cell membrane, producing alterations in membrane functions and permeability. In Candida albicans, azole antifungals inhibit transformation of blastospores into invasive mycelial form.
High dose Ketoconazole therapy may interfere with conversion of lanosterol to cholesterol, a major precursor of several hormones. It has been shown to suppress corticosteroid secretion and lower serum testosterone concentrations, which return to baseline values when Ketoconazole is discontinued.
Pharmacokinetics: Bioavailability (%): 75 (with food); VolD: 0.36 L/kg.
Serum concentrations (CSF): <10%.
Protein binding: 99%.
Half-life (hr): Normal renal function- 8.
Time to peak serum concentration (hr): 1-4.
Peak serum concentration after dose: 3.5 mcg/mL; dose-200 mg (with food).
Renal excretion (% unchanged): 2-4.
Biliary excretion: Yes; primary route of elimination.
Well distributed; distributed to inflamed joint fluid, saliva, bile, urine, breast milk, sebum, cerumen, feces, tendons, skin and soft tissue, and testes (small amounts); crosses the placenta; crosses the blood-brain barrier poorly; only negligible amounts reach the CSF. Although concentrations of 2.2 to 3 mcg per mL have been reported in the CSF with corresponding serum concentrations of 9 to 12 mcg per mL, most studies indicate that CSF concentrations >1 mcg per mL are rare, regardless of dose.