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Pharmacology: Fluconazole, a member of a new class of triazole antifungal agents, is a potent and specific inhibitor of fungal sterol synthesis. Fluconazole is highly specific for fungal cytochrome P-450 dependent enzymes. Fluconazole 50 mg daily given up to 28 days has been shown to affects testosterone plasma concentrations in males or steroid 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.
Microbiology: Fluconazole was active in a variety of animal fungal infection models. 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. Fluconazole is highly specific for fungal cytochrome P-450 dependent enzymes. Fluconazole 50 mg daily given up to 28 days has been shown not to affect testerone plasma concentrations in males or steroid 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. After oral administration fluconazole is well absorbed, and plasma levels (and systemic bioavailability) are >90% of the levels achieved after IV administration. Oral absorption is not affected by concomitant food intake. Peak plasma concentrations in the fasting state occur between 0.5 and 1.5 hrs post-dose with a plasma elimination half-life of approximately 30 hrs. Plasma concentrations are proportional to dose. Ninety percent steady state levels are reached by day 4-5 with multiple once daily dosing. Administration of loading dose (on day 1) of twice the usual daily dose enables plasma levels to approximate to 90% steady-state levels by day 2. The apparent volume of distribution approximates to total body water. Plasma protein binding is low (11-12%). Fluconazole achieves good penetration in all body fluids studied. The levels of fluconazole in saliva and sputum are similar to plasma levels. In patients with fungal meningitis, fluconazole levels in the CSF are approximately 8-% the corresponding plasma levels. High skin concentrations of fluconazole, above serum concentrations, are achieved in the stratum corneum, epidermis-dermis and eccrine sweat. Fluconazole accumulates in the stratum corneum. At a dose of 50 mg once daily, the concentration of fluconazole after 12 days was 73 mcg/g and 7 days after cessation of treatment the concentration was still 5.8 mcg/g. At the 150 mg once-a-week dose, the concentration of fluconazole in stratum corneum on day 7 was 23.4 mcg/g and 7 days after the second dose was still 7.1 mcg/g. Concentration of fluconazole in nails after 4 months of the 150 mg once-a-week dosing was 4.05 mcg/g in healthy and 1.8 mcg/g in diseased nails; and, fluconazole was still measurable in nail samples of 6 months after the end of therapy. The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged drug. 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, once daily and once weekly dosing for other indications. A study compared the saliva and plasma concentrations of a single fluconazole 100 mg dose administered in a capsule or in an oral suspension by rinsing and retaining in mouth for 2 min and swallowing. The maximum concentration of fluconazole in saliva after the suspension was observed 5 min after ingestion, and was 182 times higher than the maximum saliva concentration after the capsule, which occurred 4 hrs after ingestion. After about 4 hrs, the saliva concentrations of fluconazole were similar. The mean AUC0-96 in saliva was significantly greater after the suspension compared to the capsule. There was no significant difference in the elimination rate from saliva or the plasma pharmacokinetic parameters for the two formulations. The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged drug. 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.
