5-фторцитозин химические свойства, назначение, производство
Описание
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.
Химические свойства
White Crystalline Solid
Использование
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.
Показания
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.
Определение
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.
Антимикробная активность
The spectrum of activity is restricted to Candida spp., Cryptococcus
spp. and some fungi causing chromoblastomycosis.
Приобретенная устойчивость
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.
Фармацевтические приложения
A synthetic fluorinated pyrimidine available for intravenous
infusion or oral administration.
Механизм действия
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.
Фармаколо?гия
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.
Фармакокине?тика
Oral absorption: Complete
Cmax 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.
Побочные эффекты
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.
Метаболизм
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.
5-фторцитозин препаратная продукция и сырье
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