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Chapter: Modern Pharmacology with Clinical Applications: Antifungal Drugs

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Flucytosine Antifungal Drug

Chemistry and Mechanism of Action, Absorption, Distribution, Metabolism, and Excretion.

FLUCYTOSINE

 

Chemistry and Mechanism of Action

 

Flucytosine (5-flucytosine, 5-FC; Ancoban) is a fluori-nated pyrimidine analogue of cytosine that was origi-nally synthesized for possible use as an antineoplastic agent. 5-FC is converted to 5-fluorouracil inside the cell by the fungal enzyme cytosine deaminase. Subse-quently, 5-FC metabolites interfere with fungal DNA synthesis by inhibiting thymidylate synthetase. Incor-poration of these metabolites into fungal RNA may in-hibit protein synthesis.

Absorption, Distribution, Metabolism, and Excretion

 

5-FC is well absorbed orally, with greater than 90% bioavailability. The serum half-life is 3 to 5 hours, with serum levels peaking 4 to 6 hours after a single dose. The drug is widely distributed in body fluids, with cere-brospinal fluid levels 60 to 80% of serum levels.The drug also penetrates well into urine, aqueous humor, and bronchial secretions. Minimal serum protein binding al-lows more than 90% of each dose to be excreted in the urine; significant dosage reductions are required in the presence of renal impairment. 5-FC can be removed by both hemodialysis and peritoneal dialysis. 5-FC conver-sion to toxic metabolites may occur in mammalian cells to a limited extent, which accounts for 5-FC toxicity.

 

Clinical Uses

 

Flucytosine has significant antifungal activity against C. albicans, other Candida spp., C. neoformans, and the fungal organisms responsible for chromomycosis. Not considered the drug of choice for these fungal infec-tions, 5-FC does remain useful as part of combination therapy for systemic candidiasis and cryptococcal meningitis and as an alternative drug for chromomyco-sis. When it is used as monotherapy, resistance and clinical failure are common. Potential mechanisms for drug resistance include decreased fungal cell mem-brane permeability and reduced levels of fungal cytosine deaminase. Combination therapy with am-photericin B and flucytosine in the treatment of cryptococcal meningitis and deep-seated Candida in-fections, such as septic arthritis and meningitis, permits reduced dosing of amphotericin B and prevents the emergence of 5-FC resistance. When higher doses of amphotericin B are used, combination therapy with 5-FC confers no additional clinical benefit except in the treatment of Candida endophthalmitis, where tis-sue penetration remains problematic.

Adverse Effects

 

When 5-FC is prescribed alone to patients with normal renal function, skin rash, epigastric distress, diarrhea, and liver enzyme elevations can occur. When it is pre-scribed to patients with renal insufficiency or to patients receiving concurrent amphotericin B therapy, blood lev-els of 5-FC may rise, and bone marrow toxicity leading to leukopenia and thrombocytopenia is common. 5-FC serum levels should be closely monitored in patients with renal insufficiency. Because of baseline leukope-nia, 5-FC is often not tolerated by end-stage HIV-infected patients with disseminated fungal infection.

 

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