Pharmacology: Fluconazole is a member of a new class of triazole antifungal agents. It is a potent and specific inhibitor of fungal sterol synthesis.
Fluconazole is a highly selective inhibitor of fungal cytochrome P-450 sterol C-14 alphademethylation. 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. It has been shown that fluconazole 50mg daily given up to 28 days does not affect testosterone plasma concentrations in males or steroids concentrations in females of childbearing age.
Fluconazole 200 - 400 mg daily has no clinically significant effect on endogenous steroid levels or on ACTH-stimulated response in healthy male volunteers. Interaction studies with antipyrine indicate that single or multiple doses of fluconazole 50 mg do not affect its metabolism.
The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral routes. Fluconazole is well absorbed after oral administration. The bioavailability of orally administered fluconazole is more than 90% compared with intravenous administration. Oral absorption is not affected by concomitant food intake. In the fasting state, peak plasma concentrations occur between 0.5 and 1.5 hours post-dose with a plasma elimination half-life of approximately 30 hours. Fluconazole plasma concentrations are dose proportional.
Ninety percent steady-state levels are reached by day 4-5 with multiple once-daily dosing. Administration of a loading dose (on day 1) of twice the usual daily dose results in plasma concentration close to steady state by day 2. The apparent volume of distribution of fluconazole approximates to total body water. Plasma protein binding is low (11-12%).
Fluconazole shows good penetration into all body fluids studied. The concentrations of fluconazole in saliva and sputum are equal to plasma concentrations. In patients with fungal meningitis, fluconazole concentrations in the CSF are approximately 80% of the corresponding plasma concentrations.
The primary route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites. Fluconazole clearance is proportional to creatinine clearance. There is no evidence of circulating metabolites.
The long plasma elimination half-life provides the basis for single-dose therapy for vaginal candidiasis and once-daily dosing for all other indications.
Microbiology: Fluconazole administered orally and intravenously was active in variety of animal models of fungal infection. Activity has been demonstrated against opportunistic mycoses, eg infections with Candida sp, including systemic candidiasis in immunocompromised animals; with Cryptococcus neoformans, including intracranial infections; with Microsporum sp; and with Trichophyton sp. Fluconazole has also been shown to be active in animal models of endemic mycoses, including infections with Blastomyces dermatitides; with Coccidioides immitis; including intracranial infection; and with Histoplasma capsulatum in normal and immunosuppressed animals.