Mode of Action

Fluconazole is a highly selective inhibitor of fungal cytochrome P-450 sterol C-14 alpha-demethylation. Mammalian cell demethylation is much less sensitive to fluconazole inhibition. The subsequent loss of normal sterols correlates with the accumulation of 14 alpha-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole.

Pharmacokinetics and Metabolism

The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral routes. In normal volunteers, the bioavailability of orally administered fluconazole is over 90% compared with intravenous administration. Bioequivalence was established between the 100 mg tablet and both suspension strengths when administered as a single 200 mg dose.

Peak plasma concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours with a terminal plasma elimination half-life of approximately 30 hours (range: 20-50 hours) after oral administration.

In fasted normal volunteers, administration of a single oral 400 mg dose of DIFLUCAN (fluconazole) leads to a mean Cmax of 6.72 µg/mL (range: 4.12 to 8.08 µg/mL) and after single oral doses of 50-400 mg, fluconazole plasma concentrations and AUC (area under the plasma concentration-time curve) are dose proportional.

Administration of a single oral 150 mg tablet of DIFLUCAN (fluconazole) to ten lactating women resulted in a mean Cmax of 2.61 µg/mL (range: 1.57 to 3.65 µg/mL).

Steady-state concentrations are reached within 5-10 days following oral doses of 50-400 mg given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose results in plasma concentrations close to steady-state by the second day. The apparent volume of distribution of fluconazole approximates that of total body water. Plasma protein binding is low (11-12%). Following either single- or multiple-oral doses for up to 14 days, fluconazole penetrates into all body fluids studied (see table below). In normal volunteers, saliva concentrations of fluconazole were equal to or slightly greater than plasma concentrations regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum concentrations of fluconazole following a single 150 mg oral dose were equal to plasma concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole concentrations in the CSF are approximately 80% of the corresponding plasma concentrations.

A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal tissue, resulting in tissue:plasma ratios ranging from 0.94 to 1.14 over the first 48 hours following dosing.

A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal fluid, resulting in fluid:plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following dosing.

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