Fluconazole

Description

Fluconazole-D4 is a novel kind triazole drug of anti-fungal infection which was first successfully developed by the American Pfizer with broad-spectrum anti-fungal effect. It belongs to a kind of systemic anti-fungal products and has high selectivity on the inhibitory effect of the fungal cytochrome P450-dependent enzyme. It is also a kind of potent and specific inhibitor for the fungi alcohol synthesis. Fluconazole is used to treat adult neutropenic patients with invasive candidiasis (IC).

Production method

Indications

Fluconazole (Diflucan) may be better absorbed and is possibly less hepatotoxic than ketoconazole, but it is considerably more expensive, an important consideration given the required length of therapy for most cutaneous fungal diseases.

Manufacturing Process

It derives from a hydride of a 1H-1,2,4-triazole. Medium: Water; 900 mL for 200 mg/5 mL; 500 mL for 50 mg/5 mL Apparatus 2: 75 rpm Time: 30 min Mobile phase: Methanol and water (40:60). Adjust with glacial acetic acid to a pH of 3.4.

Therapeutic Function

Antifungal

Antimicrobial activity

The spectrum is limited, but includes most Candida spp., Cryptococcus spp., dermatophytes and dimorphic fungi (Blast. dermatitidis, Coccidioides spp., Hist. capsulatum and Paracoccidioides brasiliensis). Strains of C. krusei appear to be insensitive.

Biological Activity

Triazole antifungal agent. Effective against Candida strains in vitro and in vivo .

Biochem/physiol Actions

Fluconazole is an antifungal agent. It is highly selective inhibitor of fungal cytochrome P-450 sterol C-14 α-demethyllation. Fluconazole is a potent inhibitor of CYP2C9. Fluconazole interferes with fungal ergosterol synthesis and downregulates the metallothionein gene.

Pharmacology

DIFLUCAN® (fluconazole), the first of a new subclass of synthetic triazole antifungal agents, is available as tablets for oral administration, as a powder for oral suspension, and as a sterile solution for intravenous use in glass and in Viaflex® Plus plastic containers. It has good oral absorption, is well tolerated, and is preferentially taken up in keratinized tissues, reaching concentrations up to 50 times that in plasma. This allows for once-weekly dosing in most cases. Fluconazole is also active in animal infections caused by Blastomyces dermatitidis, Coccidioides immitis, Histoplasma capsulatum, and dermatophytes.

Side effects

Fluconazole is well tolerated. Nausea, vomiting, abdominal pain, diarrhea, and skin rash have been reported in fewer than 3% of patients. Asymptomatic liver enzyme elevation has been described, and several cases of drugassociated hepatic necrosis have been reported. Alopecia has been reported as a common adverse event in patients receiving prolonged high-dose therapy. Coadministration of fluconazole with phenytoin results in increased serum phenytoin levels.

Veterinary Drugs and Treatments

Fluconazole may have use in veterinary medicine in the treatment of systemic mycoses, including cryptococcal meningitis, blastomycosis, and histoplasmosis. It may also be useful for superficial candidiasis or dermatophytosis. Because of the drug’s unique pharmacokinetic qualities, it is probably more useful in treating CNS infections or fungal urinary tract infections than other azole derivatives. Fluconazole does not have appreciable effects (unlike ketoconazole) on hormone synthesis and may have fewer side effects than ketoconazole in small animals.

Metabolism

Fluconazole is metabolised only to a minor extent. Of a radioactive dose, only 11% is excreted as metabolites in the urine. The major route of excretion is renal, with approximately 80% of the administered dose appearing in the urine as unchanged medicinal product. Fluconazole clearance is proportional to creatinine clearance. There is no evidence of circulating metabolites.

Brand name

Diflucan (Pfizer).