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Identification
NameFlucytosine
Accession NumberDB01099  (APRD00299)
TypeSmall Molecule
GroupsApproved
Description

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

Structure
Thumb
Synonyms
5-FC
5-Fluorocystosine
5-Fluorocytosin
5-Fluorocytosine
5-Flurocytosine
Ancobon (tn)
Flucytosin
Flucytosine
Fluocytosine
Fluorcytosine
External Identifiers Not Available
Approved Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Ancoboncapsule250 mg/1oralValeant Pharmaceuticals North America LLC1971-11-26Not applicableUs
Ancoboncapsule500 mg/1oralCardinal Health1982-01-01Not applicableUs
Ancoboncapsule500 mg/1oralValeant Pharmaceuticals North America LLC1971-11-26Not applicableUs
Approved Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Flucytosinecapsule250 mg/1oralRising Pharmaceuticals, Inc.2011-07-15Not applicableUs
Flucytosinecapsule250 mg/1oralAvera Mc Kennan Hospital2015-03-01Not applicableUs
Flucytosinecapsule250 mg/1oralCarilion Materials Management2011-07-15Not applicableUs
Flucytosinecapsule500 mg/1oralRising Pharmaceuticals, Inc.2011-07-15Not applicableUs
Approved Over the Counter ProductsNot Available
Unapproved/Other Products Not Available
International Brands
NameCompany
AncotilMeda
FlusineTTY Biopharm
Brand mixturesNot Available
SaltsNot Available
Categories
UNIID83282DT06
CAS number2022-85-7
WeightAverage: 129.0925
Monoisotopic: 129.03383997
Chemical FormulaC4H4FN3O
InChI KeyInChIKey=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
6-amino-5-fluoro-1,2-dihydropyrimidin-2-one
SMILES
NC1=C(F)C=NC(=O)N1
Taxonomy
DescriptionThis 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.
KingdomOrganic compounds
Super ClassOrganoheterocyclic compounds
ClassDiazines
Sub ClassPyrimidines and pyrimidine derivatives
Direct ParentHalopyrimidines
Alternative Parents
Substituents
  • Pyrimidone
  • Halopyrimidine
  • Aminopyrimidine
  • Primary aromatic amine
  • Hydropyrimidine
  • Aryl halide
  • Aryl fluoride
  • Heteroaromatic compound
  • Azacycle
  • Hydrocarbon derivative
  • Primary amine
  • Organooxygen compound
  • Organonitrogen compound
  • Organofluoride
  • Organohalogen compound
  • Amine
  • Aromatic heteromonocyclic compound
Molecular FrameworkAromatic heteromonocyclic compounds
External Descriptors
Pharmacology
IndicationFor 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).
PharmacodynamicsFlucytosine 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 actionAlthough 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.
Related Articles
AbsorptionRapidly and virtually completely absorbed following oral administration. Bioavailability 78% to 89%.
Volume of distributionNot Available
Protein binding28-31%
Metabolism

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

Route of eliminationFlucytosine 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 life2.4 to 4.8 hours.
ClearanceNot Available
ToxicityOral, rat: LD50 = >15 gm/kg.
Affected organisms
  • Yeast and other fungi
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
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 )
Pharmacoeconomics
ManufacturersNot Available
Packagers
Dosage forms
FormRouteStrength
Capsuleoral250 mg/1
Capsuleoral500 mg/1
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.
PatentsNot Available
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point296 °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 Solubility1.92 mg/mLALOGPS
logP-0.24ALOGPS
logP-0.95ChemAxon
logS-1.8ALOGPS
pKa (Strongest Acidic)8.16ChemAxon
pKa (Strongest Basic)1.06ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area67.48 Å2ChemAxon
Rotatable Bond Count0ChemAxon
Refractivity38.22 m3·mol-1ChemAxon
Polarizability9.97 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
References
Synthesis Reference

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

US4703121
General ReferencesNot Available
External Links
ATC CodesD01AE21J02AX01
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelDownload (128 KB)
MSDSDownload (57.3 KB)
Interactions
Drug Interactions
Drug
Amphotericin BThe risk or severity of adverse effects can be increased when Amphotericin B is combined with Flucytosine.
ClozapineThe risk or severity of adverse effects can be increased when Flucytosine is combined with Clozapine.
CytarabineThe therapeutic efficacy of Flucytosine can be decreased when used in combination with Cytarabine.
GimeracilThe serum concentration of the active metabolites of Flucytosine can be increased when Flucytosine is used in combination with Gimeracil.
MetamizoleThe risk or severity of adverse effects can be increased when Metamizole is combined with Flucytosine.
Food InteractionsNot Available

Targets

1. DNA
Kind
Nucleotide
Organism
Human
Pharmacological action
yes
Actions
cross-linking/alkylation
General Function:
Used for biological information storage.
Specific Function:
DNA contains the instructions needed for an organism to develop, survive and reproduce.
Molecular Weight:
2.15 x 1012 Da
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
Human
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 essential for epigenetic inheritance. Associates with chromatin during G2 and M phases to maintain DNA methylation independently of replication. It is responsible for maintaining methylation patterns ...
Gene Name:
DNMT1
Uniprot ID:
P26358
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
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 ]
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Drug created on June 13, 2005 07:24 / Updated on April 22, 2014 15:59