Flucytosine

Identification

Name
Flucytosine
Accession Number
DB01099
Description

A fluorinated cytosine analog that is used as an antifungal agent.

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 129.0925
Monoisotopic: 129.03383997
Chemical Formula
C4H4FN3O
Synonyms
  • 5-FC
  • 5-Fluorocystosine
  • 5-Fluorocytosine
  • flucytosina
  • Flucytosine
  • Flucytosinum
External IDs
  • NSC-103805
  • RO 2-9915
  • RO-2-9915

Pharmacology

Indication

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).

Associated Conditions
Contraindications & Blackbox Warnings
Learn about our commercial Contraindications & Blackbox Warnings data.
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Pharmacodynamics

Flucytosine is an antimetabolite that acts as an antifungal agent with in vitro and in vivo 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.

Mechanism of action

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.

TargetActionsOrganism
ADNA
cross-linking/alkylation
Humans
UDNA (cytosine-5)-methyltransferase 1
other
Humans
UThymidylate synthase
inhibitor
Yeast
Absorption

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

Volume of distribution
Not Available
Protein binding

28-31%

Metabolism

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

Route of elimination

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.

Half-life

2.4 to 4.8 hours.

Clearance
Not Available
Adverse Effects
Learn about our commercial Adverse Effects data.
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Toxicity

Oral, rat: LD50 = >15 gm/kg.

Affected organisms
  • Yeast and other fungi
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbacavirAbacavir may decrease the excretion rate of Flucytosine which could result in a higher serum level.
AbataceptThe risk or severity of adverse effects can be increased when Flucytosine is combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Flucytosine.
AcarboseAcarbose may decrease the excretion rate of Flucytosine which could result in a higher serum level.
AceclofenacAceclofenac may decrease the excretion rate of Flucytosine which could result in a higher serum level.
AcemetacinAcemetacin may decrease the excretion rate of Flucytosine which could result in a higher serum level.
AcenocoumarolThe therapeutic efficacy of Acenocoumarol can be increased when used in combination with Flucytosine.
AcetaminophenAcetaminophen may decrease the excretion rate of Flucytosine which could result in a higher serum level.
AcetazolamideAcetazolamide may increase the excretion rate of Flucytosine which could result in a lower serum level and potentially a reduction in efficacy.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Flucytosine which could result in a higher serum level.
Additional Data Available
  • Extended Description
    Extended Description

    Extended description of the mechanism of action and particular properties of each drug interaction.

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  • Severity
    Severity

    A severity rating for each drug interaction, from minor to major.

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  • Evidence Level
    Evidence Level

    A rating for the strength of the evidence supporting each drug interaction.

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  • Action
    Action

    An effect category for each drug interaction. Know how this interaction affects the subject drug.

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Food Interactions
No interactions found.

Products

International/Other Brands
Ancotil (Meda) / Flusine (TTY Biopharm)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
AncobonCapsule500 mg/1OralCardinal Health1982-01-012013-02-28US flag
AncobonCapsule500 mg/1OralBausch Health US LLC1971-11-26Not applicableUS flag
AncobonCapsule250 mg/1OralBausch Health US LLC1971-11-26Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
FlucytosineCapsule500 mg/1OralCameron Pharmaceuticals, LLC2017-07-26Not applicableUS flag
FlucytosineCapsule250 mg/1OralVensun Pharmaceuticals, Inc.2016-08-21Not applicableUS flag
FlucytosineCapsule250 mg/1OralAurobindo Pharma Limited2020-05-01Not applicableUS flag
FlucytosineCapsule500 mg/1OralWest-Ward Pharmaceuticals Corp2017-10-17Not applicableUS flag
FlucytosineCapsule250 mg/1OralAmerican Health Packaging2018-01-15Not applicableUS flag
FlucytosineCapsule500 mg/1OralLupin Pharmaceuticals,Inc.2017-07-07Not applicableUS flag
FlucytosineCapsule250 mg/1OralAvera McKennan Hospital2015-03-012017-05-24US flag
FlucytosineCapsule250 mg/1OralOceanside Pharmaceuticals2012-01-172014-11-30US flag
FlucytosineCapsule250 mg/1OralRising Pharmaceuticals, Inc.2011-11-032019-04-30US flag
FlucytosineCapsule500 mg/1OralSigmapharm Laboratories, LLC2018-06-01Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

    Learn more
  • Product Code
    Product Code

    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
J02AX01 — FlucytosineD01AE21 — Flucytosine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as halopyrimidines. These are aromatic compounds containing a halogen atom linked to a pyrimidine ring. Pyrimidine is a 6-membered ring consisting of four carbon atoms and two nitrogen centers at the 1- and 3- ring positions.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Diazines
Sub Class
Pyrimidines and pyrimidine derivatives
Direct Parent
Halopyrimidines
Alternative Parents
Pyrimidones / Aminopyrimidines and derivatives / Hydropyrimidines / Aryl fluorides / Heteroaromatic compounds / Azacyclic compounds / Primary amines / Organopnictogen compounds / Organooxygen compounds / Organofluorides
show 2 more
Substituents
Amine / Aminopyrimidine / Aromatic heteromonocyclic compound / Aryl fluoride / Aryl halide / Azacycle / Halopyrimidine / Heteroaromatic compound / Hydrocarbon derivative / Hydropyrimidine
show 10 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
organofluorine compound, aminopyrimidine, pyrimidone, nucleoside analogue, pyrimidine antifungal drug (CHEBI:5100)

Chemical Identifiers

UNII
D83282DT06
CAS number
2022-85-7
InChI Key
XRECTZIEBJDKEO-UHFFFAOYSA-N
InChI
InChI=1S/C4H4FN3O/c5-2-1-7-4(9)8-3(2)6/h1H,(H3,6,7,8,9)
IUPAC Name
4-amino-5-fluoro-1,2-dihydropyrimidin-2-one
SMILES
NC1=C(F)C=NC(=O)N1

References

Synthesis Reference

Bernd Baasner, Erich Klauke, "Process for the preparation of 5-fluorocytosine." U.S. Patent US4703121, issued September, 1961.

US4703121
General References
Not Available
Human Metabolome Database
HMDB0015231
KEGG Drug
D00323
PubChem Compound
3366
PubChem Substance
46504735
ChemSpider
3249
BindingDB
50248003
RxNav
4451
ChEBI
5100
ChEMBL
CHEMBL1463
ZINC
ZINC000000896546
Therapeutic Targets Database
DAP001542
PharmGKB
PA449654
PDBe Ligand
1LD
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Flucytosine
PDB Entries
4r88
FDA label
Download (128 KB)
MSDS
Download (57.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3Not Yet RecruitingTreatmentHuman Immunodeficiency Virus (HIV) Infections / Meningitis, Cryptococcal1
2CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Meningitis, Cryptococcal2
2TerminatedTreatmentCryptococcal Infection Disseminated1
2TerminatedTreatmentMeningitis, Cryptococcal1
2, 3TerminatedTreatmentAnaplastic Astrocytoma (AA) / Glioblastoma Multiforme (GBM)1
2, 3Unknown StatusTreatmentHuman Immunodeficiency Virus (HIV) Infections / Meningitis, Cryptococcal1
2, 3WithdrawnTreatmentAnaplastic Astrocytoma (AA) / Glioblastomas / Oligodendrogliomas / Supratentorial Glioblastoma1
1Active Not RecruitingTreatmentAdult Anaplastic Astrocytoma / Adult Anaplastic Oligodendroglioma / Adult Giant Cell Glioblastoma / Adult Glioblastoma / Adult Gliosarcoma / Anaplastic Oligoastrocytoma / Recurrent Adult Brain Tumor1
1CompletedTreatmentAdult Anaplastic Astrocytoma / Adult Anaplastic Oligoastrocytoma / Adult Anaplastic Oligodendroglioma / Adult Brain Tumors / Adult Giant Cell Glioblastoma / Adult Glioblastoma / Adult Gliosarcoma / Adult Mixed Glioma / Recurrent Adult Brain Tumor / Recurrent Grade III Glioma / Recurrent Grade IV Glioma / Recurrent High Grade Glioma1
1CompletedTreatmentAnaplastic Astrocytoma (AA) / Anaplastic Oligoastrocytoma / Anaplastic Oligodendroglioma (AO) / Glioblastoma Multiforme (GBM)2

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Cardinal Health
  • Kaiser Foundation Hospital
  • Legacy Pharmaceuticals Packaging LLC
  • Valeant Ltd.
Dosage Forms
FormRouteStrength
Injection, solutionParenteral2.5 G/250ML
Tablet500 MG
Capsule, coatedOral500 mg
CapsuleOral250 mg/1
CapsuleOral500 mg/1
Capsule500 mg
Prices
Unit descriptionCostUnit
Ancobon 500 mg capsule45.54USD capsule
Ancobon 250 mg capsule23.09USD capsule
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)296 °CPhysProp
water solubility1.5E+004 mg/L (at 25 °C)MERCK INDEX (1996)
logP-1.1Not Available
pKa3.26BUDAVARI,S ET AL. (1996)
Predicted Properties
PropertyValueSource
Water Solubility2.14 mg/mLALOGPS
logP-0.69ALOGPS
logP-1ChemAxon
logS-1.8ALOGPS
pKa (Strongest Acidic)8.31ChemAxon
pKa (Strongest Basic)1.78ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area67.48 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity28.15 m3·mol-1ChemAxon
Polarizability10.04 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption+0.9734
Blood Brain Barrier+0.9653
Caco-2 permeable-0.606
P-glycoprotein substrateNon-substrate0.8098
P-glycoprotein inhibitor INon-inhibitor0.9304
P-glycoprotein inhibitor IINon-inhibitor0.9945
Renal organic cation transporterNon-inhibitor0.8989
CYP450 2C9 substrateNon-substrate0.8239
CYP450 2D6 substrateNon-substrate0.8854
CYP450 3A4 substrateNon-substrate0.7224
CYP450 1A2 substrateNon-inhibitor0.9045
CYP450 2C9 inhibitorNon-inhibitor0.9629
CYP450 2D6 inhibitorNon-inhibitor0.9669
CYP450 2C19 inhibitorNon-inhibitor0.918
CYP450 3A4 inhibitorNon-inhibitor0.9831
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9703
Ames testNon AMES toxic0.692
CarcinogenicityNon-carcinogens0.9287
BiodegradationNot ready biodegradable1.0
Rat acute toxicity1.9498 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9624
hERG inhibition (predictor II)Non-inhibitor0.9071
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-002r-9400000000-acd1b588a4052f6fc2dd
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-002r-9400000000-a4e7dd3c4c886861c0ea
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-000i-9200000000-b3fb9cad9c2b375b08c6
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-000i-9100000000-11fb61e55faa71878d87
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-000i-9000000000-13935b6ab4a3d8adaa08
LC-MS/MS Spectrum - LC-ESI-QFT , negativeLC-MS/MSsplash10-000i-9000000000-cd981efe159dd44555f4
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-001i-0900000000-a228aa7f5ecaf516455f
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-001i-0900000000-ec5b7f7d9f3c75649dc2
LC-MS/MS Spectrum - LC-ESI-QTOF , positiveLC-MS/MSsplash10-03e9-0900000000-15df2a7b685c4dd4ca17
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-001i-0900000000-7110f8accb80c700a2a5
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-001i-0900000000-89290e0501d587938afb
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-001i-0900000000-7248b6df062077397b61
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-001i-1900000000-df83e87e1bcbc8311be6
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-01q9-3900000000-42649a5ceee8a4619fc3
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-08gr-9800000000-8cb7a586d34dd7913561

Targets

Kind
Nucleotide
Organism
Humans
Pharmacological action
Yes
Actions
Cross-linking/alkylation
DNA is the molecule of heredity, as it is responsible for the genetic propagation of most inherited traits. It is a polynucleic acid that carries genetic information on cell growth, division, and function. DNA consists of two long strands of nucleotides twisted into a double helix and held together by hydrogen bonds. The sequence of nucleotides determines hereditary characteristics. Each strand serves as the template for subsequent DNA replication and as a template for mRNA production, leading to protein synthesis via ribosomes.
References
  1. Osterman DG, DePillis GD, Wu JC, Matsuda A, Santi DV: 5-Fluorocytosine in DNA is a mechanism-based inhibitor of HhaI methylase. Biochemistry. 1988 Jul 12;27(14):5204-10. [PubMed:3167042]
  2. Waldorf AR, Polak A: Mechanisms of action of 5-fluorocytosine. Antimicrob Agents Chemother. 1983 Jan;23(1):79-85. [PubMed:6338821]
  3. Wyszynski MW, Gabbara S, Kubareva EA, Romanova EA, Oretskaya TS, Gromova ES, Shabarova ZA, Bhagwat AS: The cysteine conserved among DNA cytosine methylases is required for methyl transfer, but not for specific DNA binding. Nucleic Acids Res. 1993 Jan 25;21(2):295-301. [PubMed:8441637]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Other
General Function
Zinc ion binding
Specific Function
Methylates CpG residues. Preferentially methylates hemimethylated DNA. Associates with DNA replication sites in S phase maintaining the methylation pattern in the newly synthesized strand, that is ...
Gene Name
DNMT1
Uniprot ID
P26358
Uniprot Name
DNA (cytosine-5)-methyltransferase 1
Molecular Weight
183163.635 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
  3. Shieh FK, Reich NO: AdoMet-dependent methyl-transfer: Glu119 is essential for DNA C5-cytosine methyltransferase M.HhaI. J Mol Biol. 2007 Nov 9;373(5):1157-68. Epub 2007 Aug 19. [PubMed:17897676]
  4. Wyszynski MW, Gabbara S, Kubareva EA, Romanova EA, Oretskaya TS, Gromova ES, Shabarova ZA, Bhagwat AS: The cysteine conserved among DNA cytosine methylases is required for methyl transfer, but not for specific DNA binding. Nucleic Acids Res. 1993 Jan 25;21(2):295-301. [PubMed:8441637]
Kind
Protein
Organism
Yeast
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Thymidylate synthase activity
Specific Function
Not Available
Gene Name
TMP1
Uniprot ID
P12461
Uniprot Name
Thymidylate synthase
Molecular Weight
35996.01 Da
References
  1. Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. [PubMed:17139284]
  2. Imming P, Sinning C, Meyer A: Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov. 2006 Oct;5(10):821-34. [PubMed:17016423]
  3. Fox BA, Belperron AA, Bzik DJ: Stable transformation of Toxoplasma gondii based on a pyrimethamine resistant trifunctional dihydrofolate reductase-cytosine deaminase-thymidylate synthase gene that confers sensitivity to 5-fluorocytosine. Mol Biochem Parasitol. 1999 Jan 5;98(1):93-103. [PubMed:10029312]
  4. Rehemtulla A, Hamstra DA, Kievit E, Davis MA, Ng EY, Dornfeld K, Lawrence TS: Extracellular expression of cytosine deaminase results in increased 5-FU production for enhanced enzyme/prodrug therapy. Anticancer Res. 2004 May-Jun;24(3a):1393-9. [PubMed:15274300]
  5. Wang ZH, Samuels S, Gama Sosa MA, Kolodny EH: 5-Fluorocytosine-mediated apoptosis and DNA damage in glioma cells engineered to express cytosine deaminase and their enhancement with interferon. J Neurooncol. 1998 Feb;36(3):219-29. [PubMed:9524100]

Drug created on June 13, 2005 07:24 / Updated on June 12, 2020 10:51

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