플루시토신

Pharmaceuticals

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Metabolite of Capecitabine, Emtricitabine

Pharmaceuticals -> Antibiotics

Pharmaceuticals -> Anti infectives for systemic use -> Antibacterials for systemic use

In water, 1.5 g/100 mL at 25 °C

Slightly soluble in alcohol; practically insoluble in chloroform, ether

1 g in about 12 mL 0.1 N HCL

1.92e+00 g/L

>19.4 [ug/mL] (The mean of the results at pH 7.4)

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Antifungal medicines

295-297 °C (dec)

296 °C

3.26

pKa1 = 3.26; pKa2 = 10.71

This chemical does not meet GHS hazard criteria for 5.9% (4 of 68) of reports.

Warning

H361 (83.8%): Suspected of damaging fertility or the unborn child [Warning Reproductive toxicity]

P203, P280, P318, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 68 reports by companies from 12 notifications to the ECHA C&L Inventory.

Warning

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including flucytosine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.

Advice for firefighters: Wear self contained breathing apparatus for fire fighting if necessary.

Keep container tightly closed in a dry and well-ventilated place. Light sensitive. Keep in a dry place.

Store at 25 °C (77 °F); excursions permitted between 15 deg - 30 °C (59 deg - 86 °F).

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company. Contact a licensed professional waste disposal service to dispose of this material. Dissolve or mix the material with a combustible solvent and burn in a chemical incinerator equipped with an afterburner and scrubber. Contaminated packaging: Dispose of as unused product.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Evacuate personnel to safe areas. Avoid breathing dust. Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains.

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection.

Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday.

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

Eye/face protection: Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

Skin protection: Handle with gloves.

Body Protection: Impervious clothing. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face particle respirator type N100 (US) or type P3 (EN 143) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

In the management of overdosage, prompt gastric lavage or the use of an emetic is recommended. Adequate fluid intake should be maintained, by the intravenous route if necessary, since Ancobon is excreted unchanged via the renal tract. The hematologic parameters should be monitored frequently; liver and kidney function should be carefully monitored. Should any abnormalities appear in any of these parameters, appropriate therapeutic measures should be instituted. Since hemodialysis has been shown to rapidly reduce serum concentrations in anuric patients, this method may be considered in the management of overdosage. (L1712)

Invasive fungal infection is a well-known cause of morbidity and mortality in immunocompromised patients. In this study we aimed to evaluate the hepatotoxicity induced by combined therapy of flucytosine and amphotericin B, at three different doses administered to mice for 14 days: 50 mg/kg flucytosine and 300 ug/kg amphotericin B; 100 mg/kg flucytosine and 600 ug/kg amphotericin B; 150 mg/kg flucytosine and 900 ug/kg amphotericin B. Liver injuries were evaluated by analysis of optic and electron microscopy samples, changes in TNF-alpha, IL-6, and NF-kappaB inflammation markers levels of expression, and evaluation of mRNA profiles. Histological and ultrastructural analysis revealed an increase in parenchymal and portal inflammation in mice and Kupffer cells activation. Combined antifungal treatment stimulated activation of an inflammatory pathway, demonstrated by a significant dose-dependent increase of TNF-alpha and IL-6 immunoreactivity, together with mRNA upregulation. Also, NF-kappaB was activated, as suggested by the high levels found in hepatic tissue and upregulation of target genes. Our results suggest that antifungal combined therapy exerts a synergistic inflammatory activation in a dose-dependent manner, through NF-kappaB pathway, which promotes an inflammatory cascade during inflammation. The use of combined antifungal therapy needs to be dose limiting due to the associated risk of liver injury, especially for those patients with hepatic dysfunction.

In some in vitro studies, the combination of flucytosine and amphotericin B resulted in synergistic inhibition of strains of Cryptococcus neoformans, Candida albicans, and C. tropicalis. The suggested mechanism of this synergism is that the binding of amphotericin B to sterols in cell membranes increases the permeability of the cytoplasmic membrane, thus allowing greater penetration of flucytosine into the fungal cell. However, in a study evaluating the antifungal effects of the drugs in the presence of serum, the combination of amphotericin B and flucytosine was not additive or synergistic against C. albicans. Concomitant use of amphotericin B and flucytosine may increase the toxicity of flucytosine, possibly by increasing cellular uptake and/or by decreasing renal excretion of the drug. If flucytosine is used in conjunction with amphotericin B, especially in HIV-infected patients, serum flucytosine concentrations and blood cell counts should be carefully monitored.

In in vitro studies, the combination of flucytosine and fluconazole or itraconazole was synergistic, additive, or indifferent against Cryptococcus neoformans; there was no evidence of antagonism. The combination of fluconazole and flucytosine generally did not exert a synergistic effect against C. neoformans isolates that had fluconazole MICs of 8 ug/mL or greater. Synergism also has been demonstrated when the combination of fluconazole and flucytosine was evaluated in vivo in a murine model of cryptococcal meningitis. It has been suggested that synergism between the drugs may occur because fluconazole damages the fungal cell membrane allowing greater intracellular penetration of flucytosine.

Cytarabine (cytosine arabinoside) reportedly antagonizes the antifungal activity of flucytosine, possibly by competitive inhibition. Concomitant use of the drugs is not recommended.

Transient mild-to-moderate elevations in serum aminotransferase or alkaline phosphatase levels occur in up to 41% of patients treated with flucytosine. The enzyme abnormalities are usually asymptomatic and resolve with stopping flucytosine, and sometimes even with its continuation. Clinically apparent hepatotoxicity is very rare. Instances of acute liver injury and hepatic failure have been mentioned in clinical trials of flucytosine therapy, but few details were provided and no convincing case reports of acute hepatic injury with jaundice have been published.

IDENTIFICATION AND USE: Flucytosine is a solid. It is used as antifungal agent and antimetabolite. Flucytosine Capsules are indicated only in the treatment of serious infections caused by susceptible strains of Candida and/or Cryptococcus. HUMAN STUDIES: It is reasonable to expect that overdosage may produce pronounced manifestations of the known clinical adverse reactions. Prolonged serum concentrations in excess of 100 ug/mL may be associated with an increased incidence of toxicity, especially gastrointestinal (diarrhea, nausea, vomiting), hematologic (leukopenia, thrombocytopenia) and hepatic (hepatitis). A case of urinary crystalluria was reported in a patient during treatment with flucytosine. Flucytosine-associated diarrhea has been described in 6%-10% of patients receiving the drug. A potentially fatal ulcerating enterocolitis has been reported in 4 patients. ANIMAL STUDIES: In mice, 400 mg/kg/day of flucytosine administered on days 7 to 13 of gestation was associated with a low incidence of cleft palate that was not statistically significant. Flucytosine was not teratogenic in rabbits up to a dose of 100 mg/kg/day administered on days 6 to 18 of gestation. Flucytosine was shown to be teratogenic (vertebral fusions) in the rat at doses of 40 mg/kg/day administered on days 7 to 13 of gestation. At higher doses (700 mg/kg/day) administered on days 9 to 12 of gestation), cleft lip and palate and micrognathia were reported. The in utero treatment had no adverse effect on the fertility or reproductive performance of the offspring in mice. The mutagenic potential of flucytosine was evaluated in Ames-type studies with five different mutants of Salmonella typhimurium and no mutagenicity was detected in the presence or absence of activating enzymes. Flucytosine was nonmutagenic in three different repair assay systems.

Flucytosine toxicity can present with hepatitis and gastrointestinal symptoms such as diarrhea, nausea, and vomiting. More severe symptoms, such as leukopenia and thrombocytopenia, can also develop. The adverse effects and toxicity of flucytosine are concentration-dependent and can be managed by decreasing the dosage or discontinuing the medication if complications arise. If severe toxicity does occur, the drug is manageable through hemodialysis or peritoneal dialysis, as 97% of the drug is excreted through glomerular filtration of the kidneys.

Although the exact mode of action is unknown, it has been proposed that flucytosine acts directly on fungal organisms by competitive inhibition of purine and pyrimidine uptake and indirectly by intracellular metabolism to 5-fluorouracil. Flucytosine enters the fungal cell via cytosine permease; thus, flucytosine is metabolized to 5-fluorouracil within fungal organisms. The 5-fluorouracil is extensively incorporated into fungal RNA and inhibits synthesis of both DNA and RNA. The result is unbalanced growth and death of the fungal organism. It also appears to be an inhibitor of fungal thymidylate synthase.

EPA has released the Interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides an interactive tool to explore rapid, automated (or in vitro high-throughput) chemical screening data generated by the Toxicity Forecaster (ToxCast) project and the federal Toxicity Testing in the 21st century (Tox21) collaboration. /The title compound was tested by ToxCast and/or Tox21 assays/[USEPA; ICSS Dashboard Application; Available from, as of March 27, 2018: http://actor.epa.gov/dashboard/]

/HUMAN EXPOSURE STUDIES/ The aim of this study is to investigate whether fluorouracil (5-FU) could be responsible for bone-marrow depression occurring in fluorocytosine (5-FC) treated patients. Six 5-FC treated patients were included in this pilot study. Toxicity was monitored by means of thrombocyte and leucocyte counts. 5-FC and 5-FU serum levels were measured using a high-performance liquid chromatography (HPLC) assay that allows simultaneous determination of both compounds. The amounts of 5-FU in the 34 available serum samples remained below the limit of quantitation (< 0.05 mg/L), whereas 5-FC levels could be detected in all samples. Instead, low levels of the 5-FU catabolite alpha-fluoro-beta-alanine (FBAL) were detected in several of the investigated serum samples. In case of three patients thrombocyte counts remained within the normal range during 5-FC treatment, whereas one patient developed thrombocytopenia (50 x 10(9) thrombocytes/L) during therapy. Furthermore, one patient developed leucocytopenia (2.6 x 10(9) leucocytes/L) during 5-FC therapy, whereas the remaining five patients were suffering from leucocytosis prior to 5-FC therapy. In conclusion, we found nondetectable 5-FU serum concentrations (< 0.05 mg/L) in ICU patients treated with intravenous 5-FC, making it unlikely that 5-FC-associated toxicity results from 5-FU exposure in patients receiving intravenous 5-FC therapy. These findings may be explained by the fact that our patients received 5-FC intravenously instead of orally, therefore not allowing active conversion of 5-FC to 5-FU by the human intestinal microflora. /5-Fluorouracil/

/HUMAN EXPOSURE STUDIES/ A gas chromatographic-mass spectrometric method for detecting 5-fluorouracil (5-FU) in serum at concentrations as low as 10 ng/mL was used to determine to what extent 5-FU was present in the serum of patients taking oral 5-fluorocytosine (5-FC). Preliminary studies in two patients and two healthy volunteers given an initial 2-g oral dose of 5-FC demonstrated sustained serum 5-FU levels (>100 ng/mL) during the 5 hr after ingestion of drug. Pharmaceutical preparations of 5-FC used in these studies were shown to be insignificantly contaminated with 5-FU (<0.03%), suggesting in vivo conversion of 5-FC to 5-FU had occurred. Serum samples from seven patients with cryptococcal meningitis treated with amphotericin B and 5-FC were examined for 5-FU. Five of these patients had experienced hematological or other toxicity attributed to 5-FC at some time during the course of therapy. Of 41 serum samples, 20 were observed to have 5-FU levels greater than 1,000 ng/mL in the range observed with cancer chemotherapeutic doses of 5-FU known to be associated with hematological toxicity. It is concluded that conversion of 5-FC to 5-FU occurs in humans and furthermore that 5-FU may account for some of the toxicity observed with 5-FC. /5-Fluorouracil/

/SIGNS AND SYMPTOMS/ Bone marrow toxicity occurred in 4 of 15 patients treated with 5-fluorocytosine (5-FC) for serious fungal infections. The development of marrow toxicity appeared to be related to serum 5-FC levels of 125 ug/mL or greater. In three patients, accumulation of toxic levels of 5-FC was related to diminished renal function. One patient with acute renal failure and prolonged high levels of 5-FC developed marrow aplasia and died of bacterial sepsis. Three patients experienced leukopenia, which was readily reversed when the dosage of 5-FC was decreased and the serum concentration was lowered. With careful monitoring of serum 5-FC concentration and renal function, the dose-related toxic effects of 5-FC on the marrow can be avoided.

/SIGNS AND SYMPTOMS/ There is no experience with intentional overdosage. It is reasonable to expect that overdosage may produce pronounced manifestations of the known clinical adverse reactions. Prolonged serum concentrations in excess of 100 ug/mL may be associated with an increased incidence of toxicity, especially gastrointestinal (diarrhea, nausea, vomiting), hematologic (leukopenia, thrombocytopenia) and hepatic (hepatitis).

For more Human Toxicity Excerpts (Complete) data for Flucytosine (11 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Flucytosine

Ambiguous-DILI-concern

3

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Invasive fungal infection is a well-known cause of morbidity and mortality in immunocompromised patients. In this study we aimed to evaluate the hepatotoxicity induced by combined therapy of flucytosine and amphotericin B, at three different doses administered to mice for 14 days: 50 mg/kg flucytosine and 300 ug/kg amphotericin B; 100 mg/kg flucytosine and 600 ug/kg amphotericin B; 150 mg/kg flucytosine and 900 ug/kg amphotericin B. Liver injuries were evaluated by analysis of optic and electron microscopy samples, changes in TNF-alpha, IL-6, and NF-kappaB inflammation markers levels of expression, and evaluation of mRNA profiles. Histological and ultrastructural analysis revealed an increase in parenchymal and portal inflammation in mice and Kupffer cells activation. Combined antifungal treatment stimulated activation of an inflammatory pathway, demonstrated by a significant dose-dependent increase of TNF-alpha and IL-6 immunoreactivity, together with mRNA upregulation. Also, NF-kappaB was activated, as suggested by the high levels found in hepatic tissue and upregulation of target genes. Our results suggest that antifungal combined therapy exerts a synergistic inflammatory activation in a dose-dependent manner, through NF-kappaB pathway, which promotes an inflammatory cascade during inflammation. The use of combined antifungal therapy needs to be dose limiting due to the associated risk of liver injury, especially for those patients with hepatic dysfunction.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ In mice, 400 mg/kg/day of flucytosine (1380 mg/sq m/day or 0.236 times the human dose) administered on days 7 to 13 of gestation was associated with a low incidence of cleft palate that was not statistically significant.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Flucytosine was not teratogenic in rabbits up to a dose of 100 mg/kg/day (1423 mg/sq m/day or 0.243 times the human dose) administered on days 6 to 18 of gestation.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Flucytosine was shown to be teratogenic (vertebral fusions) in the rat at doses of 40 mg/kg/day (298 mg/sq m/day or 0.051 times the human dose) administered on days 7 to 13 of gestation. At higher doses (700 mg/kg/day; 5208 mg/sq m/day or 0.89 times the human dose administered on days 9 to 12 of gestation), cleft lip and palate and micrognathia were reported.

For more Non-Human Toxicity Excerpts (Complete) data for Flucytosine (8 total), please visit the HSDB record page.

Flucytosine capsules must be given with extreme caution to patients with bone marrow depression. Patients may be more prone to depression of bone marrow function if they: 1) have a hematologic disease, 2) are being treated with radiation or drugs which depress bone marrow, or 3) have a history of treatment with such drugs or radiation. Bone marrow toxicity can be irreversible and may lead to death in immunosuppressed patients. Frequent monitoring of hepatic function and of the hematopoietic system is indicated during therapy.

Flucytosine capsules must be given with extreme caution to patients with impaired renal function. Since flucytosine capsules are excreted primarily by the kidneys, renal impairment may lead to accumulation of the drug. flucytosine capsules serum concentrations should be monitored to determine the adequacy of renal excretion in such patients. Dosage adjustments should be made in patients with renal insufficiency to prevent progressive accumulation of active drug.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including flucytosine, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

D - Dermatologicals

J - Antiinfectives for systemic use

QJ - Antiinfectives for systemic use

QD - Dermatologicals

J02AX01

Flucytosine is an antimetabolite that acts as an antifungal agent with <i>in vitro</i> and <i>in vivo</i> activity against Candida and Cryptococcus. Flucytosine enters the fungal cell via cytosine permease; thus, flucytosine is metabolized to 5-fluorouracil within fungal organisms. The 5-fluorouracil is extensively incorporated into fungal RNA and inhibits synthesis of both DNA and RNA. The result is unbalanced growth and death of the fungal organism. Antifungal synergism between Ancobon and polyene antibiotics, particularly amphotericin B, has been reported.

Although the exact mode of action is unknown, it has been proposed that flucytosine acts directly on fungal organisms by competitive inhibition of purine and pyrimidine uptake and indirectly by intracellular metabolism to 5-fluorouracil. Flucytosine enters the fungal cell via cytosine permease; thus, flucytosine is metabolized to 5-fluorouracil within fungal organisms. The 5-fluorouracil is extensively incorporated into fungal RNA and inhibits synthesis of both DNA and RNA. The result is unbalanced growth and death of the fungal organism. It also appears to be an inhibitor of fungal thymidylate synthase.

Flucytosine may be fungistatic or fungicidal in action depending on the concentration of the drug. Two possible mechanisms of action have been identified for flucytosine. Flucytosine appears to enter fungal cells via the action of fungal-specific cytosine permease. Inside the cell, flucytosine is converted into fluorouracil (5-FU) by cytosine deaminase and then after several intermediate steps is converted into 5-fluorouridine triphosphate (FUTP). FUTP is incorporated into fungal RNA and interferes with protein synthesis. Flucytosine also appears to be converted to 5-fluorodeoxyuridine monophosphate, which noncompetitively inhibits thymidylate synthetase and interferes with DNA synthesis. Flucytosine does not appear to have antineoplastic activity.

2.4 to 4.8 hours.

In a limited number of infants, the median half-life of flucytosine was 7.4 hours.

The half-life of flucytosine is prolonged in patients with renal insufficiency; the average half-life in nephrectomized or anuric patients was 85 hours (range: 29.9 to 250 hours). A linear correlation was found between the elimination rate constant of flucytosine and creatinine clearance.

The elimination half-life of flucytosine has been variously reported to be 2.4-6 hours in patients with normal renal function, 6-14 hours in patients with creatinine clearances of 40 mL/minute, 12-15 hours in patients with creatinine clearances of 20 mL/minute, 21-27 hours in patients with creatinine clearances of 10 mL/minute, and 30-250 hours in patients with creatinine clearances less than 10 mL/minute. Half-lives up to 1160 hours have been reported in a few patients with creatinine clearances less than 2 mL/minute. Some clinicians have suggested that the half-life of flucytosine in hours is approximately 5 or 6 times the serum creatinine concentration in mg/dL.

Flucytosine is deaminated, possibly by gut bacteria or by the fungal targets, to 5-fluorouracil, the active metabolite.

Flucytosine may be fungistatic or fungicidal in action depending on the concentration of the drug. Two possible mechanisms of action have been identified for flucytosine. Flucytosine appears to enter fungal cells via the action of fungal-specific cytosine permease. Inside the cell, flucytosine is converted into fluorouracil (5-FU) by cytosine deaminase and then after several intermediate steps is converted into 5-fluorouridine triphosphate (FUTP). FUTP is incorporated into fungal RNA and interferes with protein synthesis. Flucytosine also appears to be converted to 5-fluorodeoxyuridine monophosphate, which noncompetitively inhibits thymidylate synthetase and interferes with DNA synthesis. Flucytosine does not appear to have antineoplastic activity.

The aim of this study is to investigate whether fluorouracil (5-FU) could be responsible for bone-marrow depression occurring in fluorocytosine (5-FC) treated patients. Six 5-FC treated patients were included in this pilot study. Toxicity was monitored by means of thrombocyte and leucocyte counts. 5-FC and 5-FU serum levels were measured using a high-performance liquid chromatography (HPLC) assay that allows simultaneous determination of both compounds. The amounts of 5-FU in the 34 available serum samples remained below the limit of quantitation (< 0.05 mg/L), whereas 5-FC levels could be detected in all samples. Instead, low levels of the 5-FU catabolite alpha-fluoro-beta-alanine (FBAL) were detected in several of the investigated serum samples. In case of three patients thrombocyte counts remained within the normal range during 5-FC treatment, whereas one patient developed thrombocytopenia (50 x 10(9) thrombocytes/L) during therapy. Furthermore, one patient developed leucocytopenia (2.6 x 10(9) leucocytes/L) during 5-FC therapy, whereas the remaining five patients were suffering from leucocytosis prior to 5-FC therapy. In conclusion, we found nondetectable 5-FU serum concentrations (< 0.05 mg/L) in ICU patients treated with intravenous 5-FC, making it unlikely that 5-FC-associated toxicity results from 5-FU exposure in patients receiving intravenous 5-FC therapy. These findings may be explained by the fact that our patients received 5-FC intravenously instead of orally, therefore not allowing active conversion of 5-FC to 5-FU by the human intestinal microflora. /5-Fluorouracil/

A gas chromatographic-mass spectrometric method for detecting 5-fluorouracil (5-FU) in serum at concentrations as low as 10 ng/mL was used to determine to what extent 5-FU was present in the serum of patients taking oral 5-fluorocytosine (5-FC). Preliminary studies in two patients and two healthy volunteers given an initial 2-g oral dose of 5-FC demonstrated sustained serum 5-FU levels (>100 ng/mL) during the 5 hr after ingestion of drug. Pharmaceutical preparations of 5-FC used in these studies were shown to be insignificantly contaminated with 5-FU (<0.03%), suggesting in vivo conversion of 5-FC to 5-FU had occurred. Serum samples from seven patients with cryptococcal meningitis treated with amphotericin B and 5-FC were examined for 5-FU. Five of these patients had experienced hematological or other toxicity attributed to 5-FC at some time during the course of therapy. Of 41 serum samples, 20 were observed to have 5-FU levels greater than 1,000 ng/mL in the range observed with cancer chemotherapeutic doses of 5-FU known to be associated with hematological toxicity. It is concluded that conversion of 5-FC to 5-FU occurs in humans and furthermore that 5-FU may account for some of the toxicity observed with 5-FC. /5-Fluorouracil/

Metabolism of 5-fluorocytosine-6-14C (5-FC) was studied in mice, rats, rabbits and dogs after oral and subcutaneous, single and repeated administration. In the urines of all species, intact 5-FC accounted for more than 90% of the total radioactivity at any time of the various treatment schedules. The average proportion of the urinary metabolites was around 5% in dogs, 3% in rabbits, 2.5% in rats, and 2% in mice of the total radioactivity. At repeated dosage, there was an increase of metabolites in mice but a decrease in rats treated subcutaneously. Neither increase nor decrease was observed in rabbits (treated orally) and dogs. Two metabolites were identified, alpha-fluoro-beta-ureido-propionic acid (FUPA) and alpha-fluoro-beta-alanine, the latter occurring mainly after oral treatment. These compounds represent probably that part of 5-FC which was deaminated to 5-fluorouracil (5-FU) or directly to 5-fluorodihydrouracil. FUPA was the only metabolite found in the urines collected from 4 out of 5 human volunteers during the first 12 h after single oral administration of 3.5 g of the radiolabelled drug. Its maximum proportion was 1.1% of the total radioactivity. No metabolites were detected in the urine neither of the 5th volunteer nor in those of 3 mycosis patients who were given the radioactive dose after they had received regular chemotherapy with unlabelled 5-FC (150 mg/kg/day) for at least 2 weeks. The sensitivity threshold of the method was 0.1-0.4% of the total radioactivity. One of the patients had developed thrombocytopenia which was probably due to 5-FC chemotherapy. The symptoms of 5-FC intolerance were in most of the examined species similar to those observed with 5-FU [9]. However, no quantitative correlation between proportion of metabolites and 5-FC toxicity is apparent except that man is the species in which both metabolism and toxicity are the lowest. It has not been proved yet that 5-FC intolerance occurring in a small percentage of patients receiving 5-FC chemotherapy (mainly leukopenia, thrombocytopenia) results in fact from conversion to 5-FU.

For more Metabolism/Metabolites (Complete) data for Flucytosine (6 total), please visit the HSDB record page.

D83282DT06

FLUCYTOSINE

Nucleoside Analog [EXT]

Established Pharmacologic Class [EPC] - Nucleoside Analog Antifungal

Flucytosine is a Nucleoside Analog Antifungal.

FLUCYTOSINE

Substances that destroy fungi by suppressing their ability to grow or reproduce. They differ from FUNGICIDES, INDUSTRIAL because they defend against fungi present in human or animal tissues.

Drugs that are chemically similar to naturally occurring metabolites, but differ enough to interfere with normal metabolic pathways. (From AMA Drug Evaluations Annual, 1994, p2033)

Rapidly and virtually completely absorbed following oral administration. Bioavailability 78% to 89%.

Flucytosine is excreted via the kidneys by means of glomerular filtration without significant tubular reabsorption. A small portion of the dose is excreted in the feces.

Flucytosine is rapidly and well absorbed from the GI tract, with plasma levels peaking in 1-2 hr in animals that have received the drug for several days. The drug is widely distributed in the body, with a volume of distribution approximating the total body water. Flucytosine is minimally bound to plasma proteins. There is excellent penetration into body fluids such as the CSF, synovial fluids, and aqueous humor.

Flucytosine is rapidly and almost completed absorbed from the GI tract. Bioavailability is 78-89% following oral administration. Food decreases the rate, but not the extent, of absorption.

In a limited number of neonates receiving oral flucytosine in a dosage of 25, 50, or 100 mg/kg daily for the treatment of systemic candidiasis, median peak serum concentrations after 5 days of treatment were 19.6, 27.7, and 83.9 ug/mL, respectively, and the mean time to peak concentrations was 2.5 hours. There was considerable interindividual variation in serum concentrations, which did not correlate with gestational age, and some neonates had serum flucytosine concentrations greater than 100 ug/mL.

In patients with normal renal function, peak serum flucytosine concentrations of 30-40 mcg/mL are reached within 2 hours following a single 2-g oral dose. In other studies in patients with normal renal function receiving a 6-week regimen of oral flucytosine (150 mg/kg daily given in divided doses every 6 hours) and concomitant IV amphotericin B, mean serum concentrations of flucytosine 1-2 hours after a dose were approximately 70-80 ug/mL.

Antifungal Agents; Antimetabolites

MEDICATION (VET)

MEDICATION

Use (kg; approx.) in Germany (2009): >10

For the treatment (in combination with amphotericin B) of serious infections caused by susceptible strains of Candida (septicemia, endocarditis and urinary system infections) and/or Cryptococcus (meningitis and pulmonary infections).

5-Fluorouracil is reacted with POCl3 to form 2, 4-dichloro-5-fluoropyrimidine which is reacted with NH3 to produce 2-chloro-4-amino-5-fluoropyrimidine. Heating the latter in concentrated HCl yields flucytosine.

Preparation: ... R. Duschinsky, C. Heidelberger, United States of America patent 2945038 (1960 to Hoffmann-La Roche) ... .