FLUCYTOSINE

Chemistry - A fluorinated pyrimidine antifungal agent, flucytosine occurs as a white to off-white, crystalline powder that is odorless or has a slight odor with pKas of 2.9 and 10.71. It is sparinglysoluble in water and slightly soluble in alcohol. Flucytosine may also be known as 5-fluorocytosineor 5-FC.

Storage, Stability, Compatibility

Store flucytosine capsules in tight, light-resistant containers attemperatures less than 40°C, and preferably at room temperature (15-30°C). The commerciallyavailable capsules are assigned an expiration date of 5 years from the date of manufacture.

Pharmacology - FLUCYTOSINE

Flucytosine penetrates fungal cells where it is deaminated by cytosine deaminaseto fluorouracil. Fluorouracil acts as an antimetabolite by competing with uracil, thereby interferingwith pyrimidine metabolism and eventually RNA and protein synthesis. It is also thought thatflucytosine is converted to fluorodeoxyuredylic acid that inhibits thmidylate synthesis andultimately DNA synthesis.
In human cells, cytosine deaminase is apparently not present or only has minimal activity. Ratsapparently metabolize some of the drug to fluorouracil, which may explain the teratogenic effectsseen in this species. It is unclear how much cytosine deaminase activity dog and cat cells possess.
Uses, Indications - Flucytosine is principally active against strains of Cryptococcus and Candida.
When used alone, resistance can develop quite rapidly to flucytosine, particularly with
Cryptococcus. Some cases of subcutaneous and systemic chromoblastosis may also respond toflucytosine.

Pharmacokinetics - FLUCYTOSINE

Flucytosine is well absorbed after oral administration. The rate, but not extentof absorption will be decreased if given with food.
Flucytosine is distributed widely throughout the body. CSF concentrations may be 60-100% of those found in the serum. In healthy humans, the volume of distribution is about 0.7 L/kg. Only about 2-4% of the drug is bound to plasma proteins. It is unknown if flucytosine is distributed into milk.
Absorbed flucytosine is excreted basically unchanged in the urine via glomerular filtration. In humans, the half-life is about 3-6 hours in patients with normal renal function, but may be significantly prolonged in patients with renal dysfunction.

Contraindications, Precautions, Reproductive Safety

Flucytosine is contraindicated in pa-tients hypersensitive to it.
Flucytosine should be used with extreme caution in patients with renal impairment. Some clinicians recommend monitoring serum flucytosine levels in these patients and adjusting dosage (or dosing interval) to maintain serum levels at less than 100 micrograms/ml. One clinician (Macy 1987), recommends dividing the flucytosine dose by the serum creatinine level if azotemia develops.
Use flucytosine with extreme caution in patients with preexisting bone marrow depression, hematologic diseases, or receiving other bone marrow suppressant drugs. Flucytosine should alsobe used cautiously (with enhanced monitoring) in patients with hepatic disease.
Flucytosine has caused teratogenic effects in rats. It should be used in pregnant animals when thebenefits of therapy outweigh the risks.

Adverse Effects, Warnings

Adverse effects that may be seen with flucytosine include bonemarrow depression (anemia, leukopenia, thrombocytopenia), GI disturbances (nausea, vomiting, diarrhea), cutaneous eruption and rash, oral ulceration and increased levels of hepatic enzymes.
Reports of aberrant behavior and seizures in a cat without concurrent CNS infection have also beennoted after flucytosine use.

Overdosage, Acute Toxicity

No specifics regarding flucytosine overdosage was located. It issuggested that a substantial overdose be handled with gut emptying, charcoal and cathartic administration unless contraindicated.

Drug Interactions

When used with amphotericin B, synergism against Cryptococcus and Candida has been demonstrated in vitro. Toxicity of flucytosine may be enhanced however, secondary to amphotericin-caused diminished renal function and flucytosine accumulation. If clinical y significant renal toxicity develops, flucytosine dosage may need to be adjusted.Drug/Laboratory Interactions - When determining serum creatinine using the Ektachem® analyzer, false elevations in levels may be noted if patients are also taking flucytosine.