Flucytosine (5-fluorocytosine) is a fluorinated pyrimidine, or fluoropyrimidine, related to fluorouracil. It was initially developed as an antineoplastic agent and is the only systemic antifungal belonging to this class. It should be stored in airtight containers protected from light. Solutions for infusion are unstable and should be stored at 15°–20°C. Usually, it is administered orally in capsules.
Antifungal Activity
Mode of Action of Fluoropyrimidines in Animals
Flucytosine has no intrinsic antifungal activity, and its fungistatic activity is dependent on metabolism to active metabolites. Flucytosine is converted by cytosine deaminase in fungal cells to fluorouracil, which then interferes with RNA and protein synthesis. Fluorouracil is metabolized to 5-fluorodeoxyuridylic acid, an inhibitor of thymidylate synthetase. DNA synthesis is then halted. Therefore, any cells that lack cytosine deaminase are not susceptible to flucytosine. Mammalian cells lack cytosine deaminase and, thus, are not affected at usual dosage levels.
Fungal Resistance to Fluoropyrimidines in Animals
Resistance to flucytosine can develop rapidly even during the course of treatment; this precludes its use as the sole treatment for mycotic infections. The mechanisms of resistance are not completely understood; however, they may involve defects in cytosine permease or alterations in metabolic enzymes.
Antifungal Spectra of Fluoropyrimidines in Animals
The following are the main organisms usually sensitive to flucytosine: C neoformans, Candida albicans, other Candida spp, Torulopsis glabrata, S schenckii, Aspergillus spp, and agents of chromoblastomycosis (Phialophora, Cladosporium). The other fungi responsible for systemic mycoses and dermatophytes are resistant to flucytosine.
Pharmacokinetic Features
Absorption and Distribution of Fluoropyrimidines in Animals
Flucytosine can be administered orally or intravenously. Flucytosine is rapidly and well absorbed from the GI tract, with plasma levels peaking in 1–2 hours in animals that have received the drug for several days. The drug is widely distributed in the body, with a volume of distribution approximating the total body water. Flucytosine is minimally bound to plasma proteins. There is excellent penetration into body fluids such as the CSF, synovial fluids, and aqueous humor.
Biotransformation and Excretion of Fluoropyrimidines in Animals
Nearly all (85%–95%) of an oral dose of flucytosine is excreted unchanged. Flucytosine is principally excreted by glomerular filtration (>80%). The clearance of flucytosine is approximately equivalent to that of creatinine. In renal failure, elimination of flucytosine is markedly impaired.
Pharmacokinetics of Fluoropyrimidines in Animals
With normal renal function, the plasma half-life of flucytosine is usually 2–4 hours but may be up to 200 hours with oliguria. Serum levels of 50–100 mcg/mL are usually in the therapeutic range.
Therapeutic Indications and Dose Rates
The more common indications for flucytosine include cryptococcal meningitis, administered together with amphotericin B (~30% of isolates develop resistance during the course of treatment); candidiasis (~90% of isolates are usually sensitive); aspergillosis (some strains are sensitive at < 5 mcg/mL); chromomycosis (some strains are very sensitive); and sporotrichosis (some cases may respond).
General dosages for flucytosine are 25–50 mg/kg and 30–40 mg/kg, PO, every 6 to 8 hours in dogs and cats, respectively. The dose rate and frequency should be adjusted as needed for the individual animal. Dosage modification is essential in renal failure. Flucytosine serum levels should be monitored if possible.
Special Clinical Concerns
Adverse Effects and Toxicity of Fluoropyrimidines in Animals
Flucytosine is often well tolerated over long periods, but toxic effects may be seen when serum levels are high (>100 mcg/mL). These include GI signs (nausea, vomiting, diarrhea) and reversible hepatic and hematologic effects (increased liver enzymes, anemia, neutropenia, thrombocytopenia). In dogs, erythemic and alopecic dermatitis may be seen, but it subsides when the drug is discontinued.
Interactions of Fluoropyrimidines in Animals
There is synergistic antifungal activity between amphotericin B and flucytosine, and the combination may retard the emergence of strains resistant to flucytosine. The renal effects of amphotericin B prolong elimination of flucytosine. If flucytosine is administered together with immunosuppressive drugs, severe depression of bone marrow function is possible.
Effects on Laboratory Tests of Fluoropyrimidines in Animals
Treatment with flucytosine increases alkaline phosphatase, AST, ALT, and other liver leakage enzymes, and decreases RBC, WBC, and platelet counts.
