Flucytosin

Gefahreninformationscode (GHS)

• Bildanzeige (GHS)

  

• Alarmwort

  Warnung

• Gefahrenhinweise

  H361：Kann vermutlich die Fruchtbarkeit beeinträchtigen oder das Kind im Mutterleib schädigen.

• Sicherheit

  P280：Schutzhandschuhe/Schutzkleidung/Augenschutz tragen.

Fluorocytosine Chemische Eigenschaften,Einsatz,Produktion Methoden

• R-Sätze Betriebsanweisung:

  R40:Verdacht auf krebserzeugende Wirkung.
  R36/37/38:Reizt die Augen, die Atmungsorgane und die Haut.

• S-Sätze Betriebsanweisung:

  S22:Staub nicht einatmen.
  S24/25:Berührung mit den Augen und der Haut vermeiden.
  S45:Bei Unfall oder Unwohlsein sofort Arzt zuziehen (wenn möglich, dieses Etikett vorzeigen).
  S36/37:Bei der Arbeit geeignete Schutzhandschuhe und Schutzkleidung tragen.
  S36/37/39:Bei der Arbeit geeignete Schutzkleidung,Schutzhandschuhe und Schutzbrille/Gesichtsschutz tragen.
  S27:Beschmutzte, getränkte Kleidung sofort ausziehen.
  S26:Bei Berührung mit den Augen sofort gründlich mit Wasser abspülen und Arzt konsultieren.

• Beschreibung

  5-Fluorocytosine (5-FC), a fluorinated pyrimidine analog, is a synthetic antimycotic prodrug that is converted by cytosine deaminase to 5-fluorouracil. 5-Fluorouracil, a widely used cytotoxic drug, is further metabolized to fluorinated ribo- and deoxyribonucleotides, resulting in the inhibition of DNA and protein synthesis, which has multiple effects including inhibition of Candida species and C. neoformans infections and cytotoxicity towards cancer cells. In combination with a retroviral replicating vector carrying a cytosine deaminase prodrug-activating gene, 5-FC has been shown to selectively eliminate CT26 and Tu-2449 tumor cells in vitro (IC₅₀s = 4.2 and 1.5 μM, respectively) and to significantly improve survival and reduce tumor size (at a dose of 500 mg/kg) in two different syngeneic mouse glioma models.

• Chemische Eigenschaften

  White Crystalline Solid

• Originator

  Ancobon,Roche,US,1972

• Verwenden

  5-FC is a toxic antifungal/antimicrobial agent

• Verwenden

  5-Fluorocytosine acts as an antidiabetic, antifungal and antimicrobial agent. It is useful for the treatment of serious infections arises due to susceptible strains of Candida or Cryptococcus neoformans and chromomycosis. Further, it is employed in studies on TMP biosynthesis.

• Indications

  Flucytosine (Ancobon) is a synthetic, fluorinated pyrimidine that is structurally related to fluorouracil (FU) and floxuridine. It can be fungistatic and fungicidal. Although it is used more frequently in the treatment of systemic infections caused by Candida and Cryptococcus, dermatologic indications may include infections due to chromomycosis, sporotrichosis, Cladosporium, and Sporothrix species. It is generally ineffective against Aspergillus species.

• Definition

  ChEBI: Flucytosine is an organofluorine compound that is cytosine that is substituted at position 5 by a fluorine. A prodrug for the antifungal 5-fluorouracil, it is used for the treatment of systemic fungal infections. It has a role as a prodrug. It is an organofluorine compound, a pyrimidone, an aminopyrimidine, a nucleoside analogue and a pyrimidine antifungal drug. It is functionally related to a cytosine.

• Manufacturing Process

  The preparation of 5-fluorouracil is given under "Fluorouracil." As described in US Patent 3,040,026, 5-fluorouracil is then subjected to the following steps to give flucytosine.
  Step 1: 2,4-Dichloro-5-Fluoropyrimidine - A mixture of 104 grams (0.8 mol) of 5-fluorouracil, 1,472 grams (9.6 mols) of phosphorus oxychloride and 166 grams (1.37 mols) of dimethylaniline was stirred under reflux for 2 hours. After cooling to room temperature, phosphorus oxychloride was removed by distillation at 18 to 22 mm and 22° to 37°C. The residue was then poured into a vigorously stirred mixture of 500 ml of ether and 500 gram of ice. After separating the ether layer, the aqueous layer was extracted with 500 ml, then 200 ml of ether. The combined ether fractions were dried over sodium sulfate, filtered, and the ether removed by vacuum distillation at 10° to 22°C. The residue, a yellow solid melting at 37° to 38°C, weighed 120 grams corresponding to a 90% yield. Vacuum distillation of 115 grams of this material at 74° to 80°C (16 mm) gave 108 grams of white solid melting at 38° to 39°C corresponding to an 84.5% yield.
  Step 2: 2-Chloro-4-Amino-5-Fluoropyrimidine - To a solution of 10.0 grams (0.06 mol) of 2,4-dichloro-5-fluoropyrimidine in 100 ml of ethanol, 25 ml of concentrated aqueous ammonia were slowly added. A slightly opalescent solution resulted. The temperature gradually rose to 35°C. The solution was then cooled in ice to 18°C and thereafter remained below 30°C. After three hours, a Volhard titration showed that 0.0545 mol of chlorine was present in ionic form. Storage in a refrigerator overnight resulted in some crystallization of ammonium chloride. A white sludge, resulting from the evaporation of the reaction mixture at 40°C, was slurried with 75 ml of water, filtered and washed free of chloride. After drying in vacuo, the product melted at 196.5° to 197.5°C, yield 6.44 grams. Evaporation of the mother liquors yielded a second crop of 0.38 gram, raising the total yield to 6.82 grams (79.3%).
  Step 3: 5-Fluorocytosine - A slurry of 34.0 grams (0.231 mol) of 2-chloro-4- amino-5-fluoropyrimidine in 231 ml of concentrated hydrochloric acid was heated in a water bath at 93° to 95°C for 125 minutes. The reaction was followed by means of ultraviolet spectrophotometry using the absorption at 245, 285, and 300 mμ as a guide. The absorption at 300 mμ rose to a maximum after 120 minutes and then dropped slightly. The clear solution was cooled to 25°C in an ice bath, then evaporated to dryness under vacuum at 40°C. After slurrying with water three times and reevaporating, the residue was dissolved in 100 milliliters of water. To this solution, cooled in ice, 29 ml of concentrated ammonia were added dropwise. The resulting precipitate was filtered, washed free of chloride with water, then with alcohol and ether. After drying in vacuo at 65°C, the product weighed 22.3 grams. An additional 6.35 grams was obtained by evaporation of the mother liquor, thus yielding a total of 28.65 grams (96.0%).

• Trademarks

  Ancobon (Valeant).

• Therapeutic Function

  Antifungal

• Antimicrobial activity

  The spectrum of activity is restricted to Candida spp., Cryptococcus spp. and some fungi causing chromoblastomycosis.

• Acquired resistance

  About 2–3 of Candida spp. isolates (more in some centers) are resistant before treatment starts, and resistance may develop during treatment. The most common cause of resistance appears to be loss of the enzyme uridine monophosphate pyrophosphorylase.

• Pharmazeutische Anwendungen

  A synthetic fluorinated pyrimidine available for intravenous infusion or oral administration.

• Biochem/physiol Actions

  Nucleoside analog that has antifungal activities. 5-FC is deaminated by cytosine deaminase to product 5-fluorouracil, resulting in RNA miscoding. 5-Fluorocytosine inhibits DNA and RNA synthesis and interferes with ribosomal protein synthesis.

• Mechanism of action

  Flucytosine (5-flucytosine, 5-FC; Ancoban) is a fluorinated pyrimidine analogue of cytosine that was originally synthesized for possible use as an antineoplastic agent. It is indicated only for the treatment of serious systemic infections caused by susceptible strains of Candida and Cryptococcus spp.The mechanism of action of 5-fluorocytosine (5-FC)has been studied in detail.The drug enters the fungal cell by active transport onATPases that normally transport pyrimidines. Once insidethe cell, 5-fluorocytosine is deaminated in a reaction catalyzedby cytosine deaminase to yield 5-fluorouracil(5-FU). 5-Fluorouracil is the active metabolite of the drug.5-Fluorouracil enters into pathways of both ribonucleotideand deoxyribonucleotide synthesis. The fluororibonucleotidetriphosphates are incorporated into RNA, causingfaulty RNA synthesis. This pathway causes cell death. Inthe deoxyribonucleotide series, 5-fluorodeoxyuridinemonophosphate (F-dUMP) binds to 5,10-methylenetetrahydrofolicacid, interrupting the one-carbon pool substratethat feeds thymidylate synthesis. Hence, DNA synthesisis blocked.

• Pharmakologie

  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 cerebrospinal fluid levels 60 to 80% of serum levels.The drug also penetrates well into urine, aqueous humor, and bronchial secretions.Minimal serum protein binding allows 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 conversion to toxic metabolites may occur in mammalian cells to a limited extent, which accounts for 5-FC toxicity.

• Pharmakokinetik

  Oral absorption: Complete
  C_max 25 mg/kg 6-hourly oral: 70–80 mg/L after 1–2 h
  Plasma half-life: 3–6 h
  Volume of distribution: 0.7–1 L/kg
  Plasma protein binding c. 12%
  Absorption is slower in persons with impaired renal function, but peak concentrations are higher. Levels in the CSF are around 75% of the simultaneous serum concentration. More than 90% of a dose of flucytosine is excreted in the urine in unchanged form. The serum half-life is much longer in renal failure, necessitating modification of the dosage regimen: for patients with a creatinine clearance below 40 mL/ min the dosage interval should be doubled to 12 h; in severe renal failure the dosage interval should be further increased to once daily or less, based on frequent serum drug concentration measurements.

• Clinical Use

  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 infections, 5-FC does remain useful as part of combination therapy for systemic candidiasis and cryptococcal meningitis and as an alternative drug for chromomycosis. When it is used as monotherapy, resistance and clinical failure are common. Potential mechanisms for drug resistance include decreased fungal cell membrane permeability and reduced levels of fungal cytosine deaminase. Combination therapy with amphotericin B and flucytosine in the treatment of cryptococcal meningitis and deep-seated Candida infections, 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 tissue penetration remains problematic.

• Clinical Use

  Candidosis (in combination with amphotericin B or fluconazole)
  Cryptococcosis (in combination with amphotericin B or fluconazole)
  Monitoring of flucytosine concentrations is desirable in all patients, and mandatory in those with renal impairment.

• Nebenwirkungen

  Nausea, vomiting, abdominal pain and diarrhea are common. Serious side effects include myelosuppression and hepatic toxicity; they occur more frequently when serum concentrations exceed 100 mg/L.
  The nephrotoxic effects of amphotericin B can result in elevated blood concentrations of flucytosine, and levels of the latter drug should be monitored when these compounds are administered together. When 5-FC is prescribed alone to patients with normal renal function, skin rash, epigastric distress, diarrhea, and liver enzyme elevations can occur.

• Synthese

  Flucytosine, 5-fluorocytosine (35.4.4), is synthesized from fluorouracil (30.1.3.3). Fluorouracil is reacted with phosphorous oxychloride in dimethylaniline to make 2,4-dichloro-5-fluoropyrimidine (35.4.2), which is reacted with ammonia to make a product substituted with chlorine at the fourth position of the pyrimidine ring—4-amino- 2-chloro-5-fluoropyrimidine (35.4.3). Hydrolysis of the chlorovinyl fragment of this compound in a solution of hydrochloric acid gives the desired flucytosine.
  
  An alternative way of synthesis consists of making flucytosine from a precursor of fluorouracil—5-fluoro-2-methylthiouracil (30.1.3.2) using a somewhat analogous scheme. Treating 5-fluoro-2-methylthiouracil (30.1.3.2) with phosphorous pentachloride gives 4-chloro-5-fluoro-2-methylthiopyrimidine (35.4.5), which upon being reacted with ammonium is transformed into 4-amino-5-fluoro-2-methylthiopyrimidine (35.4.6). Hydrolysis of the methylthiovinyl fragment using concentrated hydrobromic acid gives the desired flucytosine.
  

• Arzneimittelwechselwirkung

  Potentially hazardous interactions with other drugs
  Cytarabine: concentration of flucytosine possibly reduced.

• Stoffwechsel

  Flucytosine itself is not cytotoxic but, rather, is a pro-drug that is taken up by fungi and metabolized to 5-fluorouracil (5-FU) by fungal cytidine deaminase. Then, 5-FU is converted to 5-fluorodeoxyuridine, which as a thymidylate synthase inhibitor interferes with both protein and RNA biosynthesis. 5-Fluorouracil is cytotoxic and is employed in cancer chemotherapy. Human cells do not contain cytosine deaminase and, therefore, do not convert flucytosine to 5-FU. Some intestinal flora, however, do convert the drug to 5-FU, so human toxicity does result from this metabolism.

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