Identification

Name
Flucytosine
Accession Number
DB01099  (APRD00299)
Type
Small Molecule
Groups
Approved, Investigational
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
  • flucytosina
  • Flucytosine
  • Fluocytosine
  • Fluorcytosine
External IDs
NSC-103805 / RO 2-9915 / RO-2-9915
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
AncobonCapsule500 mg/1OralCardinal Health1982-01-012013-02-28Us
AncobonCapsule500 mg/1OralValeant Pharmaceuticals North America1971-11-26Not applicableUs
AncobonCapsule250 mg/1OralValeant Pharmaceuticals North America1971-11-26Not applicableUs
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
FlucytosineCapsule250 mg/1OralVensun Pharmaceuticals, Inc.2016-08-21Not applicableUs
FlucytosineCapsule250 mg/1OralNovel Laboratories, Inc.2017-07-07Not applicableUs
FlucytosineCapsule250 mg/1OralOceanside Pharmaceuticals2012-01-172014-11-30Us
FlucytosineCapsule500 mg/1OralCameron Pharmaceuticals2017-07-26Not applicableUs
FlucytosineCapsule500 mg/1OralRising Pharmaceuticals2011-11-03Not applicableUs
FlucytosineCapsule250 mg/1OralAmerincan Health Packaging2018-01-15Not applicableUs
FlucytosineCapsule250 mg/1OralLupin Pharmaceuticals2017-07-07Not applicableUs
FlucytosineCapsule250 mg/1OralWest-Ward Pharmaceuticals Corp2017-10-17Not applicableUs
FlucytosineCapsule500 mg/1OralSigma Pharm Laboratories, Llc2018-06-01Not applicableUs
FlucytosineCapsule250 mg/1OralAvera McKennan Hospital2015-03-012018-05-21Us
International/Other Brands
Ancotil (Meda) / Flusine (TTY Biopharm)
Categories
UNII
D83282DT06
CAS number
2022-85-7
Weight
Average: 129.0925
Monoisotopic: 129.03383997
Chemical Formula
C4H4FN3O
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
6-amino-5-fluoro-1,2-dihydropyrimidin-2-one
SMILES
NC1=C(F)C=NC(=O)N1

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
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
Human
UDNA (cytosine-5)-methyltransferase 1
other
Human
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
Toxicity

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

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

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of bleeding can be increased when (R)-warfarin is combined with Flucytosine.
(S)-WarfarinThe risk or severity of bleeding can be increased when (S)-Warfarin is combined with Flucytosine.
2-MethoxyethanolThe risk or severity of adverse effects can be increased when Flucytosine is combined with 2-Methoxyethanol.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when 4-hydroxycoumarin is combined with Flucytosine.
9-(N-methyl-L-isoleucine)-cyclosporin AThe risk or severity of adverse effects can be increased when Flucytosine is combined with 9-(N-methyl-L-isoleucine)-cyclosporin A.
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.
AbetimusThe risk or severity of adverse effects can be increased when Flucytosine is combined with Abetimus.
AcenocoumarolThe risk or severity of bleeding can be increased when Acenocoumarol is combined with Flucytosine.
Acetylsalicylic acidThe risk or severity of bleeding can be increased when Acetylsalicylic acid is combined with Flucytosine.
Food Interactions
Not Available

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
External Links
Human Metabolome Database
HMDB0015231
KEGG Drug
D00323
PubChem Compound
3366
PubChem Substance
46504735
ChemSpider
3249
BindingDB
50241247
ChEBI
5100
ChEMBL
CHEMBL1463
Therapeutic Targets Database
DAP001542
PharmGKB
PA449654
HET
1LD
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Flucytosine
ATC Codes
D01AE21 — FlucytosineJ02AX01 — Flucytosine
PDB Entries
4r88
FDA label
Download (128 KB)
MSDS
Download (57.3 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1Active Not RecruitingTreatmentAdult Anaplastic Astrocytoma / Adult Anaplastic Oligodendroglioma / Adult Giant Cell Glioblastoma / Adult Glioblastoma / Adult Gliosarcoma / Anaplastic Oligoastrocytoma / Recurrent Adult Brain Tumor1
1Active Not RecruitingTreatmentBladder Cancers / Brain Metastasis / Cancer of the Ovary / Colorectal Cancers / Head and Neck Carcinoma / IDH1 Mutated or MGMT Methylated Recurrent HGG (Not Recruiting) / IDH1 Mutated or MGMT Methylated Recurrent High Grade Glioma / IDH1 Mutated Solid Tumors / Locally Advanced or Metastatic Breast Cancer / Locally Advanced or Metastatic Pancreatic Cancer / Lung Cancer Non-Small Cell Cancer (NSCLC) / Malignant Lymphomas / Malignant Neoplasm of Pancreas / Melanoma / Metastatic Colorectal Cancers / Metastatic Melanoma / Metastatic Renal Cell Carcinoma / Sarcomas / Triple Negative Breast Cancer (TNBC)1
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) / Glioblastomas1
1CompletedTreatmentHepatocellular,Carcinoma1
1Not Yet RecruitingTreatmentNewly Diagnosed High Grade Glioma (HGG)1
1, 2RecruitingTreatmentBrain Cancer / Glioblastomas1
1, 2RecruitingTreatmentDigestive System Neoplasms / Malignant Neoplasm of Colon1
1, 2RecruitingTreatmentMalignancies / Neoplasms / Tumors1
2CompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Meningitis, Cryptococcal2
2TerminatedTreatmentCryptococcal Infection Disseminated1
2, 3Active Not RecruitingTreatmentHuman Immunodeficiency Virus (HIV) / Meningitis, Cryptococcal1
2, 3RecruitingTreatmentAnaplastic Astrocytoma (AA) / Glioblastoma Multiforme (GBM)1
Not AvailableCompletedTreatmentHuman Immunodeficiency Virus (HIV) Infections / Meningitis, Cryptococcal5

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Cardinal Health
  • Kaiser Foundation Hospital
  • Legacy Pharmaceuticals Packaging LLC
  • Valeant Ltd.
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.
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 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 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

Taxonomy

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
Aminopyrimidine / Halopyrimidine / Pyrimidone / Aryl fluoride / Aryl halide / Hydropyrimidine / Heteroaromatic compound / Azacycle / Amine / Primary amine
show 10 more
Molecular Framework
Aromatic heteromonocyclic compounds
External Descriptors
organofluorine compound, aminopyrimidine, pyrimidone, nucleoside analogue, pyrimidine antifungal drug (CHEBI:5100)

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 ...
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 November 02, 2018 04:55