Diflucan

[Fluconazole]

Clinical Pharmacology
CLINICAL PHARMACOLOGY

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.

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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 µ g/ mL (range: 4.12 to 8.08 µ g/ 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 µ g/ mL (range: 1.57 to 3.65 µ g/ 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).

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