Flucytosine is a prodrug that is converted intracellularly to 5-fluorouracil (5-FU), which inhibits fungal RNA and DNA synthesis. The active metabolites inhibit thymidylate synthetase (a key enzyme in DNA synthesis) and are incorporated into RNA in place of uridylic acid, disrupting protein synthesis.

Flucytosine exhibits antifungal activity primarily against yeasts and some dematiaceous fungi. The MICs for susceptible fungal species (e.g., Candida, Cryptococcus, Torulopsis, Phialophora, Cladosporium, Aspergillus spp.) range from 0.1 to approximately 25 mg/L.
For other fungi such as Emmonsia, Madurella, Pyrenochaeta, Cephalosporium, Sporothrix, and Blastomyces dermatitidis, MICs are much higher, ranging from 100 to 1000 mg/L.
The antifungal activity is not intrinsic but depends on its uptake by fungal cells via cytosine permease and subsequent intracellular conversion to 5-fluorouracil (5-FU) by the enzyme cytosine deaminase.
The mechanism of action involves two pathways after conversion to 5-FU: 1) Incorporation of 5-fluorouridine triphosphate (FUTP) into fungal RNA, disrupting protein synthesis; and 2) Conversion to 5-fluorodeoxyuridine monophosphate (FdUMP), a potent inhibitor of thymidylate synthetase, thereby inhibiting DNA synthesis. [1]

In animal models, flucytosine has shown activity in experimental candidosis and cryptococcosis in mice.
Clinical studies in humans (non-HIV and HIV-infected patients) have demonstrated the efficacy of flucytosine in combination with amphotericin B for the treatment of cryptococcal meningitis, leading to increased rates of cerebrospinal fluid sterilization and decreased mortality compared to monotherapy.
The combination of amphotericin B and flucytosine is also used for treating systemic candidosis (including meningitis, endophthalmitis, endocarditis, peritonitis), chromoblastomycosis, and phaeohyphomycosis of the central nervous system.
For invasive aspergillosis, flucytosine is sometimes added to amphotericin B, although clear evidence of superior efficacy over amphotericin B alone is lacking. [1]

A cytosine deaminase conversion assay was performed in vitro using thin-layer chromatography (TLC) to analyze the enzymatic activity of CD expressed in transfected hMSC (CD-hMSC). CD-hMSC or non-transfected hMSC were lysed by repeated freezing and thawing. The cell supernatant was incubated with 5-FC to initiate the conversion reaction. Aliquots of the reaction mixture were spotted onto a TLC plate and developed in a butanol:water (86:14) solvent system to separate 5-FU from 5-FC. Standards of 5-FC and 5-FU were used for comparison. The conversion ratio was quantified by scanning the TLC plate and analyzing the spots with appropriate software.[2]

An in vitro migration assay was conducted to assess the ability of hMSC to migrate towards MKN45 gastric cancer cells. The assay was performed using Matrigel-coated invasion chambers. hMSC were seeded in the upper chamber, while MKN45 cells, NIH3T3 fibroblasts, or HaCaT keratinocytes were placed in the lower chamber as targets or controls. After 24 hours of incubation, cells that migrated through the Matrigel were stained and counted. Fluorescently labeled hMSC (with red dye) were also used to visually confirm migration towards target cells (labeled with green dye) under fluorescence microscopy.[2]
A cytotoxicity assay was performed by co-culturing MKN45 cells and CD-hMSC in 96-well plates. After 24 hours of co-culture, the medium was replaced with serum-free medium containing either 5-FC or PBS (control). Cell viability was assessed using the MTT assay. MTT solution was added to the cells and incubated for 4 hours. The resulting formazan crystals were dissolved in acidic isopropanol, and the optical density was measured at 550 nm.[2]

To establish tumor xenografts, 2x10^6 MKN45 human gastric cancer cells suspended in 200 µL of HBSS were inoculated subcutaneously into the flanks of 7-week-old female athymic nude mice.[2]
When tumor volumes reached approximately 130 mm^3, mice were divided into treatment groups. For the therapeutic experiment, groups receiving CD-hMSC were intravenously injected with 2x10^6 CD-hMSC suspended in 200 µL of HBSS via the lateral tail vein. One day later, systemic treatment with flucytosine (5-FC) was initiated. 5-FC was administered intraperitoneally at a dose of 500 mg/kg/day for 7 consecutive days. Tumor growth was monitored by caliper measurements every day, and tumor volume was calculated using the formula V = (L x W^2) x 0.5.[2]
In a separate experiment to track hMSC migration in vivo, mice bearing 4-day-old MKN45 tumors were intravenously injected with 1x10^6 fluorescently labeled hMSC. Mice were euthanized at 24 or 72 hours post-injection, and tumors and major organs were harvested for fluorescence microscopy examination to locate the labeled hMSC.[2]

Absorption, Distribution and Excretion
Flucytosine is rapidly and almost completely absorbed after oral administration. Its bioavailability is 78% to 89%. Flucytosine is primarily excreted through the kidneys via glomerular filtration; tubular reabsorption is minimal. Small doses are excreted in feces. Flucytosine is rapidly and well absorbed from the gastrointestinal tract; in animals given the drug for several consecutive days, peak plasma concentrations are reached within 1-2 hours. The drug is widely distributed throughout the body, with a volume of distribution approaching the total body fluid volume. Flucytosine has extremely low binding to plasma proteins. It penetrates well into body fluids such as cerebrospinal fluid, synovial fluid, and aqueous humor. Flucytosine is rapidly and almost completely absorbed from the gastrointestinal tract. Its bioavailability after oral administration is 78-89%. Food may slow the absorption rate but does not affect the extent of absorption. In a small number of neonates receiving oral flucytosine (25, 50, or 100 mg/kg daily) for systemic candidiasis, the median peak serum concentrations after 5 days of treatment were 19.6, 27.7, and 83.9 μg/mL, respectively, with a mean time to peak concentration of 2.5 hours. Significant individual variability in serum concentrations was observed, independent of gestational age, with some neonates achieving serum flucytosine concentrations exceeding 100 μg/mL. In patients with normal renal function, a single oral dose of 2 g of flucytosine resulted in peak serum concentrations of 30-40 μg/mL within 2 hours. In other studies, patients with normal renal function receiving 6 weeks of oral flucytosine (150 mg/kg daily, divided doses every 6 hours) combined with intravenous amphotericin B showed mean serum flucytosine concentrations of approximately 70-80 μg/mL 1-2 hours after administration. For more complete data on the absorption, distribution, and excretion of flucytosine (8 items in total), please visit the HSDB record page.

---

Metabolism/Metabolites
Fluorcytosine may be deaminated to its active metabolite, 5-fluorouracil, via intestinal bacterial or fungal targets. The action of flucytosine may depend on drug concentration, exhibiting either antibacterial or bactericidal effects. Two possible mechanisms of action for flucytosine have been identified. Flucytosine appears to enter fungal cells via fungal-specific cytosine permeases. Intracellularly, flucytosine is converted to fluorouracil (5-FU) by cytosine deaminase, and then to 5-fluorouridine triphosphate (FUTP) via several intermediate steps. FUTP can be incorporated into fungal RNA, interfering with protein synthesis. Flucytosine also appears to be converted to 5-fluorodeoxyuridine monophosphate, which non-competitively inhibits thymidylate synthase, interfering with DNA synthesis. Flucytosine does not appear to possess antitumor activity. This study aimed to investigate whether fluorouracil (5-FU) was the cause of myelosuppression in patients treated with fluorocytosine (5-FC). This preliminary study included six patients receiving 5-FC treatment. Toxicity was monitored by platelet and white blood cell counts. Serum concentrations of 5-FC and 5-FU were determined using high-performance liquid chromatography (HPLC), a method that simultaneously measures both compounds. In 34 available serum samples, 5-fluorouracil (5-FU) levels were below the limit of quantitation (< 0.05 mg/L), while 5-fluorocytosine (5-FC) was detectable in all samples. Furthermore, low levels of the 5-FU metabolite α-fluoro-β-alanine (FBAL) were detected in some serum samples. Platelet counts remained within the normal range in three patients during 5-FC treatment, while one patient developed thrombocytopenia (50 x 10⁹ platelets/L) during treatment. In addition, one patient developed leukopenia (2.6 x 10⁹ leukocytes/L) during 5-FC treatment, while the remaining five patients had leukocytosis before 5-FC treatment. In summary, we found that the serum concentration of 5-fluorouracil (5-FU) in ICU patients receiving intravenous 5-fluorocytosine (5-FC) was below the detection limit (< 0.05 mg/L). Therefore, the 5-FC-related toxicity in patients receiving intravenous 5-FC is unlikely to be caused by 5-FU exposure. This result may be because our patients received intravenous rather than oral 5-FC, thus preventing the active conversion of 5-FC to 5-FU by the human gut microbiota. /5-Fluorouracil/
We used gas chromatography-mass spectrometry to detect serum concentrations as low as 10 ng/mL of 5-fluorouracil (5-FU) to determine the 5-FU content in the serum of patients receiving oral 5-fluorocytosine (5-FC). A preliminary study included two patients and two healthy volunteers who received an initial oral dose of 2 g of 5-fluorocytosine (5-FC). Results showed that serum 5-fluorouracil (5-FU) levels remained above 100 ng/mL for 5 hours after administration. The 5-FC formulation used in the study contained extremely low levels of 5-FU (<0.03%), suggesting that 5-FC is converted to 5-FU in the body. Researchers measured 5-FU levels in serum samples from seven patients with cryptococcal meningitis treated with amphotericin B and 5-FC. Five of these patients had experienced 5-FC-related hematologic or other toxicities during treatment. Of the 41 serum samples, 20 had 5-FU levels above 1000 ng/mL, a concentration range consistent with known concentrations of 5-FU at chemotherapy doses associated with hematologic toxicity in cancer patients. The study concludes that 5-FC is converted to 5-FU in the body, and that 5-FU may be a source of some of the toxicity of 5-FC. /5-Fluorouracil/
This study investigated the metabolism of 5-fluorocytosine-6-14C (5-FC) after oral and subcutaneous administration, as well as single and repeated administration, in mice, rats, rabbits, and dogs. In the urine of all animals, regardless of the administration regimen, intact 5-FC accounted for over 90% of the total radioactivity. The average proportions of metabolites in the urine of dogs, rabbits, rats, and mice were approximately 5%, 3%, 2.5%, and 2% of the total radioactivity, respectively. Repeated administration increased metabolite levels in mouse urine, while subcutaneous administration decreased metabolite levels in rat urine. No increase or decrease in metabolite levels was observed in the urine of rabbits and dogs after oral administration. Two metabolites were identified: α-fluoro-β-ureapropionic acid (FUPA) and α-fluoro-β-alanine, the latter appearing primarily after oral administration. These compounds may represent the deamination of 5-fluorocytosine (5-FC) to 5-fluorouracil (5-FU) or directly to 5-fluorodihydrouracil. In 4 out of 5 healthy volunteers, only FUPA metabolites were detected in urine within 12 hours after a single oral dose of 3.5 g of radiolabeled drug. The largest proportion was 1.1% of total radioactivity. No metabolites were detected in the urine of the 5th volunteer and 3 patients with fungal diseases. These 3 patients with fungal diseases received radioactive doses of 5-FC after receiving at least 2 weeks of routine unlabeled 5-FC chemotherapy (150 mg/kg/day). The sensitivity threshold of this method was 0.1% to 0.4% of total radioactivity. One of the patients developed thrombocytopenia, which may have been due to 5-fluorocytosine (5-FC) chemotherapy. In most of the tested species, the symptoms of 5-FC intolerance were similar to those of 5-fluorouracil (5-FU) intolerance [9]. However, except for humans, who have the lowest metabolic and toxicity levels, there is no clear quantitative correlation between metabolite ratios and 5-FC toxicity. It has not been confirmed that the 5-FC intolerance (primarily manifested as leukopenia and thrombocytopenia) observed in a small number of patients receiving 5-fluorocytosine (5-FC) chemotherapy is actually converted from 5-fluorouracil (5-FU). For more complete metabolite/metabolite data on flucytosine (6 metabolites), please visit the HSDB record page. Flucytosine may be deaminated to the active metabolite 5-fluorouracil via intestinal bacteria or fungal targets. Elimination pathway: Flucytosine is primarily excreted via glomerular filtration through the kidneys, with minimal tubular reabsorption. A small amount of the drug is excreted in feces. Half-life: 2.4 to 4.8 hours. Biological half-life: 2.4 to 4.8 hours. In a small number of infants, the median half-life of flucytosine is 7.4 hours. The half-life of flucytosine is prolonged in patients with renal insufficiency; the mean half-life in patients who have undergone nephrectomy or have anuria is 85 hours (range: 29.9 to 250 hours). The elimination rate constant of flucytosine is linearly correlated with creatinine clearance. It has been reported that the elimination half-life of flucytosine is 2.4–6 hours in patients with normal renal function, 6–14 hours in patients with a creatinine clearance of 40 mL/min, 12–15 hours in patients with a creatinine clearance of 20 mL/min, 21–27 hours in patients with a creatinine clearance of 10 mL/min, and 30–250 hours in patients with a creatinine clearance of less than 10 mL/min. In a small number of patients with a creatinine clearance of less than 2 mL/min, the half-life of flucytosine can reach 1160 hours. Some clinicians believe that the half-life (in hours) of flucytosine is about 5 to 6 times that of serum creatinine concentration (in mg/dL).

---

Oral absorption of flucytosine is rapid and almost complete, with a bioavailability of 76-89%. Peak serum concentrations are reached within 1-2 hours.
The drug has a small molecular weight, high water solubility, and low serum protein binding, which allows it to penetrate well into most parts of the body, including cerebrospinal fluid, vitreous fluid, peritoneal fluid, and inflamed joints.
Flucytosine is mainly excreted by the kidneys through glomerular filtration, with very little metabolism in the liver. Its plasma clearance is closely related to creatinine clearance.
In patients with normal renal function, its half-life is about 3-4 hours, but in patients with severe renal insufficiency, the half-life can be extended to 85 hours. The apparent volume of distribution is approximately equal to the total body fluid and is not significantly affected by renal failure. [1]

Toxicity Summary
Identification and Use: Flucytosine is a solid. It is an antifungal and antimetabolite. Flucytosine capsules are only indicated for the treatment of serious infections caused by susceptible Candida and/or Cryptococcal strains. Human Studies: Overdose can be reasonably expected to exacerbate known adverse clinical reactions. Prolonged serum concentrations exceeding 100 μg/mL may be associated with an increased incidence of toxicities, particularly gastrointestinal toxicities (diarrhea, nausea, vomiting), hematologic toxicities (leukopenia, thrombocytopenia), and hepatotoxicities (hepatitis). One patient has been reported to have urinary crystals during flucytosine treatment. Flucytosine-associated diarrhea has been reported in 6%–10% of patients taking the drug. Four patients have been reported to have potentially fatal ulcerative colitis. Animal Studies: In mice, administration of 400 mg/kg/day of flucytosine from day 7 to day 13 of gestation was associated with a low incidence of cleft palate, but this was not statistically significant. In rabbits, administration of 100 mg/kg/day of flucytosine during days 6 to 18 of gestation showed no teratogenicity. In rats, administration of 40 mg/kg/day of flucytosine during days 7 to 13 of gestation showed teratogenicity (vertebral fusion). Cleft lip and palate and micrognathia were reported with higher doses (700 mg/kg/day) administered during days 9 to 12 of gestation. Intrauterine administration had no adverse effects on the fertility or reproductive function of offspring in mice. In the Ames assay, the mutagenicity of flucytosine was assessed using five different Salmonella Typhimurium mutants, and no mutagenicity was detected regardless of the presence of activating enzymes. Flucytosine also did not show mutagenicity in three different repair assay systems. Although its exact mechanism of action is unclear, some studies suggest that flucytosine may act directly on fungi by competitively inhibiting the uptake of purines and pyrimidines, and indirectly through intracellular metabolism to produce 5-fluorouracil. Flucytosine enters fungal cells via cytosine permease; subsequently, it is metabolized within the fungus to 5-fluorouracil. 5-Fluorouracil is incorporated in large quantities into fungal RNA, inhibiting DNA and RNA synthesis. This ultimately leads to fungal growth imbalance and death. It also appears to be an inhibitor of fungal thymidylate synthase.
Hepatotoxicity
Up to 41% of patients treated with flucytosine experience transient, mild to moderate elevations in serum transaminases or alkaline phosphatase levels. These enzyme abnormalities are usually asymptomatic and resolve upon discontinuation of flucytosine, sometimes even with continued use. Clinically significant hepatotoxicity is very rare. Cases of acute liver injury and liver failure have been mentioned in clinical trials of flucytosine treatment, but details are scarce, and no convincing case reports of acute liver injury with jaundice have been published.
Probability Score: D (Possibly a rare cause of clinically significant liver injury). Protein Binding Rate: 28-31% Toxicity Data: LD50: 15 g/kg (oral, rat) (A308) Interactions: Invasive fungal infections are a common cause of morbidity and death in immunocompromised patients. This study aimed to evaluate the hepatotoxicity induced by combined treatment with flucytosine and amphotericin B. Mice were administered three different doses of flucytosine and amphotericin B for 14 days: 50 mg/kg flucytosine and 300 μg/kg amphotericin B; 100 mg/kg flucytosine and 600 μg/kg amphotericin B; and 150 mg/kg flucytosine and 900 μg/kg amphotericin B. Liver injury was assessed by analyzing samples using optical and electron microscopy, detecting changes in the expression levels of inflammatory markers TNF-α, IL-6, and NF-κB, and by mRNA profiling. Histological and ultrastructural analyses revealed increased inflammation in the mouse liver parenchyma and portal vein, along with Kupffer cell activation. Combined antifungal therapy stimulated activation of inflammatory pathways, manifested as a significant dose-dependent increase in TNF-α and IL-6 immunoreactivity and upregulation of mRNA. Furthermore, NF-κB was also activated, as indicated by elevated NF-κB levels and upregulation of target genes in liver tissue. Our results suggest that combined antifungal therapy exerts a synergistic inflammatory activation effect via NF-κB in a dose-dependent manner. This pathway promotes the inflammatory cascade during inflammation. Due to the risk of liver injury, especially in patients with hepatic impairment, the dosage of combined antifungal therapy needs to be limited. In some in vitro studies, the combination of flucytosine and amphotericin B synergistically inhibited the growth of Cryptococcus neoformans, Candida albicans, and Candida tropicalis. The mechanism of this synergistic effect may be that amphotericin B binds to sterols on the cell membrane, increasing cell membrane permeability and thus facilitating the penetration of flucytosine into fungal cells. However, in a study evaluating the antifungal effects of these drugs in the serum presence, the combined use of amphotericin B and flucytosine did not show an additive or synergistic effect against Candida albicans. Concomitant use of amphotericin B and flucytosine may increase the toxicity of flucytosine, possibly by increasing… Flucytosine exerts its effects by increasing cellular uptake and/or decreasing renal excretion. Serum flucytosine concentrations and blood cell counts should be closely monitored if flucytosine is used in combination with amphotericin B, especially in HIV-infected patients. In vitro studies have shown that the combined use of flucytosine with fluconazole or itraconazole has synergistic, additive, or no-differential effects against Cryptococcus neoformans; no antagonistic effects were observed. The combined use of fluconazole and flucytosine generally has no synergistic effect against Cryptococcus neoformans isolates with a fluconazole MIC ≥ 8 μg/mL. In vivo evaluation of the combined use of fluconazole and flucytosine in a mouse model of cryptococcal meningitis also confirmed its synergistic effect. Studies have shown that the synergistic effect between the drugs may be due to fluconazole disrupting the fungal cell membrane, thus making it easier for flucytosine to enter the cell. Cysine arabinoside has been reported to antagonize the antifungal activity of flucytosine, possibly through competitive inhibition. Concomitant use of these two drugs is not recommended. Non-human toxicity values: Rat subcutaneous LD50: 3600 mg/kg; Rat intraperitoneal LD50: 3811 mg/kg; Mouse intravenous LD50: 500 mg/kg; Mouse subcutaneous LD50: 1000 mg/kg; Mouse intraperitoneal LD50: 1190 mg/kg. The most common and mildest side effects of flucytosine are gastrointestinal reactions, including nausea, vomiting, diarrhea, and abdominal pain, which occur in approximately 6% of patients. Serious toxicities include hepatotoxicity (elevated liver enzymes, elevated bilirubin) and myelosuppression (leukopenia, thrombocytopenia, pancytopenia). The reported incidence of hepatotoxicity is 0-41%, and myelosuppression is closely associated with serum 5-fluorocytosine (5-FC) concentrations >100 mg/L. These serious toxicities are generally concentration-dependent, predictable, and may be reversed by dose reduction or discontinuation. Maintaining peak serum concentrations below 100 mg/L is recommended to avoid toxicity. Myelosuppression occurs in 60% of patients with 5-FC concentrations >100 mg/L, compared to 12% in patients with concentrations <100 mg/L. The toxicity mechanism may involve the conversion of fluorocytosine to 5-fluorouracil (5-FU) by the human gut microbiota, or the presence of 5-FU as an impurity in intravenous preparations. 5-FU concentrations detected in patients receiving 5-FC are comparable to concentrations known to cause hematologic disorders.
Patients with underlying hematologic disorders, impaired renal function, or concurrent use of nephrotoxic drugs (such as amphotericin B) have an increased risk.
Concurrent use of aluminum hydroxide or magnesium hydroxide suspensions can delay the absorption of flucytosine.
Due to similar absorption mechanisms, the antifungal activity of flucytosine can be competitively inhibited by cytarabine (cytarabine arabinoside). [1]

[1]. Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J Antimicrob Chemother. 2000 Aug;46(2):171-9.

[2]. Cytosine deaminase-producing human mesenchymal stem cells mediate an antitumor effect in a mouse xenograft model. J Gastroenterol Hepatol. 2009 Aug;24(8):1393-400.

[3]. Itraconazole and flucytosine+itraconazole combination in the treatment of experimental cryptococcosis in hamsters. Mycoses. 1995 Nov-Dec;38(11-12):449-52.

Therapeutic Uses

Antifungal drugs; antimetabolites
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that indexes human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov contains summary information about the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure being investigated); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (for providing patient health information) and PubMed (for providing citations and abstracts of academic articles in the medical field). Flucytosine is indexed in the database.
Fluorocytosine capsules are only indicated for the treatment of serious infections caused by Candida and/or Cryptococcal strains sensitive to flucytosine. Candida: Flucytosine is effective in treating sepsis, endocarditis, and urinary tract infections. Limited trial results for pulmonary infections support the use of flucytosine. Cryptococcus: Flucytosine is effective in treating meningitis and pulmonary infections. Studies on sepsis and urinary tract infections are limited, but good efficacy has been reported. /Included in US product label/
Due to the emergence of resistance to flucytosine capsules, flucytosine capsules should be used in combination with amphotericin B to treat systemic candidiasis and cryptococcosis. /Included in US product label/
For more complete data on the therapeutic uses of flucytosine (of 10), please visit the HSDB record page.

---

Drug Warnings
/Black Box Warning/ Use with extreme caution in patients with impaired renal function. Close monitoring of the hematological, renal, and hepatic status of all patients is essential. These instructions should be carefully read before taking flucytosine capsules (USP).
Patients with myelosuppression must take flucytosine capsules with extreme caution. The following patients may be more susceptible to myelosuppression: 1) those with hematologic disorders; 2) those receiving radiation therapy or using myelosuppressive drugs; or 3) those with a history of such drugs or radiation therapy. Myelotoxicity may be irreversible and can lead to death in immunosuppressed patients. Liver function and hematopoietic system should be monitored frequently during treatment. In addition to its antiproliferative effects on the gastrointestinal mucosa, flucytosine has been reported to cause several gastrointestinal adverse reactions, sometimes serious, including anorexia, bloating, abdominal pain, diarrhea, dry mouth, duodenal ulcers, gastrointestinal bleeding, nausea, vomiting, and ulcerative colitis. There are currently no adequate or controlled studies on the use of flucytosine in pregnant women; therefore, it should only be used during pregnancy if the potential benefit outweighs the potential risk to the fetus. For more complete (17) drug warnings for flucytosine, please visit the HSDB record page. Pharmacodynamics Flucytosine is an antimetabolite with antifungal activity against a variety of fungi, exhibiting both in vitro and in vivo activity. It is effective against Candida and Cryptococcus species. Flucytosine enters fungal cells via cytosine permease; subsequently, it is metabolized within the fungus to 5-fluorouracil. 5-fluorouracil is incorporated into fungal RNA, inhibiting DNA and RNA synthesis. This ultimately leads to fungal growth imbalance and death. It has been reported that flucytosine has a synergistic antifungal effect with polyene antibiotics, particularly amphotericin B. Fluorocytosine (5-FC) is a synthetic fluorinated pyrimidine analogue, first synthesized in 1957. It is used as an antifungal agent but is inactive on its own; it is converted into the active metabolite 5-fluorouracil (5-FU) within susceptible fungal cells as a prodrug. Due to the frequent emergence of drug resistance (approximately 10% of Candida albicans exhibits inherent resistance, up to 22% of other Candida species, and 1-2% of Cryptococcus neoformans), monotherapy is limited. It is primarily used in combination with other antifungal agents, such as amphotericin B or azoles. Clinical indications include cryptococcal meningitis, systemic candidiasis, chromoblastomycosis, and chromophilic filamentous infections. It is also being investigated for use as a novel enzyme/prodrug therapy in cancer treatment (e.g., colorectal cancer).
The dosage needs to be adjusted according to renal function: the standard dose is 37.5 mg/kg every 6 hours, which is suitable for patients with creatinine clearance >40 mL/min; for patients with creatinine clearance (CrCl) of 20-40 mL/min, the dose is 37.5 mg/kg every 12 hours; for patients with CrCl <20 mL/min, the dose is 37.5 mg/kg once daily; for patients with CrCl <10 mL/min, close monitoring is required. It is recommended to monitor the therapeutic drug, with target trough concentration and peak concentration of 25-50 mg/L and 50-100 mg/L, respectively. [1]

C4H4FN3O

129.0925

129.033

2022-85-7

Flucytosine-13C,15N2;1216616-31-7

3366

White to off-white solid powder

1.7±0.1 g/cm3

298ºC

298-300 °C (dec.)(lit.)

0.0492mmHg at 25°C

1.649

-2.36

2

3

0

9

208

0

XRECTZIEBJDKEO-UHFFFAOYSA-N

InChI=1S/C4H4FN3O/c5-2-1-7-4(9)8-3(2)6/h1H,(H3,6,7,8,9)

6-amino-5-fluoro-1H-pyrimidin-2-one

5-Fluorocytosine; NSC-103805; NSC103805; NSC 103805; Ro-2-9915; Ro2-9915; Ro 2-9915; Flucytosine, Flucytosin, Ancobon, Ancotil

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~16.67 mg/mL (~129.13 mM)
H2O : ~6.67 mg/mL (~51.67 mM)

Solubility in Formulation 1: ≥ 1.67 mg/mL (12.94 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 1.67 mg/mL (12.94 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

---

View More

Solubility in Formulation 3: ≥ 1.67 mg/mL (12.94 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

Solubility in Formulation 4: 8.67 mg/mL (67.16 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

---

 (Please use freshly prepared in vivo formulations for optimal results.)