5-flucytosine

Flucytosine (Ancobon) possesses clinically useful activity against Cryptococcus neoformans, Candida species, Torulopsis glabrata, and the agents of chromomycosis. Susceptible fungi deam-inate flucytosine to 5-fluorouracil, which becomes an antimetabolite. Flucytosine, which is excreted by the kidney, should be used cautiously in the setting of renal impairment. Flucytosine is a bone marrow depressant. Flucytosine is used in combination with amphotericin B. 

Acetic anhydride Methane sulfonyl chloride Chlorine 

To 6a-fluoro-16a-hydroxy-hydrocortisone 21-acetate, described by Mills et al, J. Am. Chem. Soc., volume 81, pages 1264 to 1265, March 5, 1959, there was added acetic anhydride in dry pyridine. The reaction mixture was left at room temperature overnight and was then poured with stirring into ice water. The resulting precipitate was filtered, washed with water and crystallized from acetone-hexane to give 6a-fluoro-16a-hydroxy-hydrocortisone-16a,21-diacetate. This was reacted with methane-sulfonyl chloride in dimethyl formamide in the presence of pyridine at 80°C for 1 hour. The mixture was cooled, diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and the ethyl acetate was evaporated. By recrystallization of the residue from acetone-hexane there was obtained 6a-fluoro-A -pregnadiene-16o ,17a,21-triol-3,20-dione 16a,21 diacetate. 

This was reacted with chlorine to give the dichloropregnene compound, then with selenium dioxide to give the dichloropregnadiene compound. By hydrolysis with methanolic potassium hydroxide there was obtained the free 6a-fluoro-9a,11/3-dichloro-A -pregnadiene-16a,-17a,21-triol-3,20-dione. By treatment with acetone in the presence of perchloric acid, the 16,17-acetonide of 6a-fluoro-9a,11/3-dichloro-A -pregnadiene 16a,17a,21-triol-3,20-dione was formed. 

Bowers, A. U.S. Patent 3,201,391 August 17, 1965 assigned to Syntex Corporation, Panama 

Therapeutic Function Antifungal Chemical Name 5-fluorocytosine Common Name — 

6a-Fluoro-16Q +iydroxycortisone-21-acetate Acetic anhydride Methane sulfonyl chloride Chlorine 

The preparation of 5-fluorouracil is given under Fluorouracil. As described in U.S. Patent 3,040,026, 5-fluorouracil is then subjected to the following steps to give flucytosine. 

Chemical Abstracts Registry No. 2022-85-7 Trade Name Manufacturer 

---

Flucytosine. Flucytosine (17) or 5-fluorocytosine (4-amino-5-fluoro-2-pyrimidone, 5-FC), C H FN O, is a pyrimidine derivative, that is efficient against Candida albicans Cryptococcus neoformans and Torulopsis glabrata. 

It is also active against A.spergillus Phialophora and Cladosporium. The x.o. ozoaA.canthamoeba culbertsoni and l ishmania are sensitive to flucytosine (1,24). 

Flucytosine [2022-85-7] is well absorbed in the digestive tract, which is why oral adraiinistration is preferable. Plasma levels of 30 —40 mg/L are obtained after a dose of 30 mg/kg body weight. Approximately 90% of the pyrimidine derivative is found unaltered in urine, indicating that it is highly suitable for the treatment of renal candidosis. High concentrations were also noted in cerebrospinal fluid the average concentration is approximately 75% of the plasma concentration. 

With the aid of cytosine permease, flucytosine reaches the fungal cell where it is converted by cytosine deaminase into 5-fluorouracil [51-21-8]. Cytosine deaminase is not present in the host, which explains the low toxicity of 5-FC. 5-Fluorouracil is then phosphorylated and incorporated into RNA and may also be converted into 5-fluorodeoxyuridine monophosphate, which is a potent and specific inhibitor of thymidylate synthetase. As a result, no more thymidine nucleotides are formed, which in turn leads to a disturbance of the DNA-synthesis. These effects produce an inhibition of the protein synthesis and cell repHcation (1,23,24). 5-Fluorouracil caimot be used as an antimycotic. It is poorly absorbed by the fungus to begin with and is also toxic for mammalian cells. 

Flucytosine-resistant strains can develop very rapidly. These mutants may have a disturbed 5-FC-metabohsm, or a compensatory mechanism for the disturbed nucleic acid functions. No cytosine permease was found in a resistant Cyptococcus neoformans strain, whereas cytosine deaminase was absent in resistant C. albicans strains. A deficiency of uridine monophosphate pyrophosphorylase occurs frequently in resistant C. albicans strains (1). 

The dosage of flucytosine is 150—200 mg/kg orally in four portions every six hours. A 1% flucytosine solution has been developed for intravenous adrninistration. In some countries, a 10% ointment is also available. In patients with normal renal function, flucytosine is seldom toxic, but occasionally severe toxicity may be observed (leukopenia and thrombocytopenia). Plasma levels should be determined and the dose in patients with impaired renal function should be checked. Liver function tests (transaininases and alkaline phosphatase) should be performed regularly. In some patients with high flucytosine plasma levels, hepatic disorders have been observed (24). 

Griseofulvin (Grisactin) exerts its effect by being deposited in keratin precursor cells, which are then gradually lost (due to the constant shedding of top skin cells), and replaced by new, noninfected cells. The mode of action of flucytosine (Ancobon) is not clearly understood. Clotrimazole (Lotrimin, Mycelex) binds with phospholipids in the fungal cell membrane,... 

Flucytosine is contraindicated in patients with known hypersensitivity to the drug. Flucytosine is used cautiously in patients with bone marrow depression and with extreme caution in those with renal impairment. The drug is also used cautiously during pregnancy (Category C) and lactation. When flucytosine and amphotericin B are administered concurrently, the risk of flucytosine toxicity is increased. 

FLUCYTOSINE The nurse gives flucytosine orally. The prescribed dose may range from 2 to 6 capsules/dose. To decrease or avoid nausea and vomiting, the capsules may be taken a few at a time during a 15-minute period. 

FLUCYTOSINE To reduce the incidence of gastrointestinal distress, the nurse may give the capsules one or two at a time during a 15-minute period. If gastrointestinal distress still occurs, the nurse should notify the primary health care provider. Before therapy is begun, electrolytes, hematological status, and renal status are... 

Flucytosine Nausea and vomiting may occur with diis drug. Reduce or eliminate these effects by taking a few capsules at a time during a 15-minute period. If nausea, vomiting, or diarrhea persists, notify die primary healdi care provider as soon as possible. 

Which of tiie following laboratory tests would the nurse monitor in patients receiving flucytosine ... 

C21H27CIFN7O2 32566-14-6) see Flurazepam 4-amino-2-chloro-5-fluoropyrimidine (C4H2CIFN3 155-10-2) see Flucytosine 4-amino-6-chloro-S-methoxypyrimidine (CjHdClNjO 5018-41-7) see Sulfadoxine... 

C 2H]7FN402 75167-28-1) see Enoxacin 4-amino-5-fluoro-2-(methylthio)pyrimidine (C H FNjS) see Flucytosine a-aminoglutarimide... 

Fig. 5.20 Imidazoles (A-F) A, metronidazole B, clotrimazole C, miconazole D, econazole E, ketoconazole F, fluconazole G, flucytosine H, 5-fluorouracil I, terbinafme J, tolnaftate.

Response rates are lower for non-albicans infections. Although an optimal regimen is unknown, use of intravaginal azole therapy for 7 to 14 days is recommended. Terconazole may prove more effective than other azoles in the treatment of non-albicans infections since C. glabrata and C. tropicalis are more susceptible to terconazole.17 For second-line therapy, boric acid 600 mg in a gelatin capsule administered vaginally twice daily for 2 weeks followed by once daily during menstruation is effective.18 Local irritation often limits the use of boric acid. Topical 4% flucytosine is also effective but use should be limited due to the potential for resistance. 

Cryptococcal meningitis is fatal if left untreated. Because pneumonia frequently precedes dissemination of disease and subsequent meningitis, all patients with culture-, histopathology-, or serology-proven disease should receive antifungal therapy. In patients with isolated pulmonary cryptococcosis, fluconazole is generally considered to be the therapy of choice (see Table 81-2).37 Alternatively, itraconazole or combination therapy (fluconazole plus flucytosine) has also been used with some success in patients. 

---