FLUCYTOSINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C4H4FN3O
Molecular Weight	129.0925
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

NC1=NC(=O)NC=C1F

InChI

InChIKey=XRECTZIEBJDKEO-UHFFFAOYSA-N

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

HIDE SMILES / InChI

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017001s027lbl.pdf
Curator's Comment: Description was created using several sources including: http://www.uptodate.com/contents/pharmacology-of-flucytosine-5-fc; http://www.ncbi.nlm.nih.gov/pubmed/6338821; http://www.ncbi.nlm.nih.gov/pubmed/10933638

Flucytosine (5-flucytosine, Ancobon) is an antifungal agent used for treatment of serious fungal infections caused by Candida or Cryptococcus. A fluorinated cytosine analog it was originally developed as an anti-tumor agent, but was found to be non-effective against tumors. Monotherapy with 5-FC is limited because of the frequent development of pathogens resistance. It is often used in in combination with amphotericin B. The severe side effects of 5-flucytosine include hepatotoxicity and bone-marrow depression. 5-fluorocytosine is a prodrug to the cytotoxic compound 5-fluorouracil. 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 is taken up by fungal organisms via the enzyme cytosine permease. Inside the fungal cell, flucytosine is rapidly converted to fluorouracil by the enzyme cytosine deaminase. Fluorouracil exerts its antifungal activity through the subsequent conversion into several active metabolites, which inhibit protein synthesis by being falsely incorporated into fungal RNA or interfere with the biosynthesis of fungal DNA through the inhibition of the enzyme thymidylate synthetase.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Thymidylate synthase 32 Target ID: CHEMBL2364680 Sources: http://www.drugbank.ca/drugs/DB01099	Inhibitor 8297
Thymidylate synthase 32 Target ID: CHEMBL4665 Sources: http://www.drugbank.ca/drugs/DB01099	Inhibitor 8297

Conditions

Condition	Modality	Highest Phase	Product
Candida endocarditis 1 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017001s027lbl.pdf	Curative	Approved 8429	ANCOBON Approved Use INDICATIONS & USAGE Flucytosine Capsules is indicated only in the treatment of serious infections caused by susceptible strains of Candida and/or Cryptococcus. Candida: Septicemia, endocarditis and urinary system infections have been effectively treated with flucytosine. Limited trials in pulmonary infections justify the use of flucytosine. Cryptococcus: Meningitis and pulmonary infections have been treated effectively. Studies in septicemias and urinary tract infections are limited, but good responses have been reported. Flucytosine Capsules should be used in combination with amphotericin B for the treatment of systemic candidiasis and cryptococcosis because of the emergence of resistance to Flucytosine Capsules (see MICROBIOLOGY). Launch Date 1971
Systemic candidiasis 1 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017001s027lbl.pdf	Curative	Approved 8429	ANCOBON Approved Use INDICATIONS & USAGE Flucytosine Capsules is indicated only in the treatment of serious infections caused by susceptible strains of Candida and/or Cryptococcus. Candida: Septicemia, endocarditis and urinary system infections have been effectively treated with flucytosine. Limited trials in pulmonary infections justify the use of flucytosine. Cryptococcus: Meningitis and pulmonary infections have been treated effectively. Studies in septicemias and urinary tract infections are limited, but good responses have been reported. Flucytosine Capsules should be used in combination with amphotericin B for the treatment of systemic candidiasis and cryptococcosis because of the emergence of resistance to Flucytosine Capsules (see MICROBIOLOGY). Launch Date 1971
Cryptococcal meningitis 3 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017001s027lbl.pdf	Curative	Approved 8429	ANCOBON Approved Use INDICATIONS & USAGE Flucytosine Capsules is indicated only in the treatment of serious infections caused by susceptible strains of Candida and/or Cryptococcus. Candida: Septicemia, endocarditis and urinary system infections have been effectively treated with flucytosine. Limited trials in pulmonary infections justify the use of flucytosine. Cryptococcus: Meningitis and pulmonary infections have been treated effectively. Studies in septicemias and urinary tract infections are limited, but good responses have been reported. Flucytosine Capsules should be used in combination with amphotericin B for the treatment of systemic candidiasis and cryptococcosis because of the emergence of resistance to Flucytosine Capsules (see MICROBIOLOGY). Launch Date 1971
Cryptococcus pulmonary infections 1 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017001s027lbl.pdf	Curative	Approved 8429	ANCOBON Approved Use INDICATIONS & USAGE Flucytosine Capsules is indicated only in the treatment of serious infections caused by susceptible strains of Candida and/or Cryptococcus. Candida: Septicemia, endocarditis and urinary system infections have been effectively treated with flucytosine. Limited trials in pulmonary infections justify the use of flucytosine. Cryptococcus: Meningitis and pulmonary infections have been treated effectively. Studies in septicemias and urinary tract infections are limited, but good responses have been reported. Flucytosine Capsules should be used in combination with amphotericin B for the treatment of systemic candidiasis and cryptococcosis because of the emergence of resistance to Flucytosine Capsules (see MICROBIOLOGY). Launch Date 1971
Candida urinary system infections 1 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017001s027lbl.pdf	Curative	Approved 8429	ANCOBON Approved Use INDICATIONS & USAGE Flucytosine Capsules is indicated only in the treatment of serious infections caused by susceptible strains of Candida and/or Cryptococcus. Candida: Septicemia, endocarditis and urinary system infections have been effectively treated with flucytosine. Limited trials in pulmonary infections justify the use of flucytosine. Cryptococcus: Meningitis and pulmonary infections have been treated effectively. Studies in septicemias and urinary tract infections are limited, but good responses have been reported. Flucytosine Capsules should be used in combination with amphotericin B for the treatment of systemic candidiasis and cryptococcosis because of the emergence of resistance to Flucytosine Capsules (see MICROBIOLOGY). Launch Date 1971

C_max

Value	Dose	Co-administered	Analyte	Population
57.3 mg/L EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/20038612	1500 mg single, oral dose: 1500 mg route of administration: Oral experiment type: SINGLE co-administered:		FLUCYTOSINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
506 mg × h/L EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/20038612	1500 mg single, oral dose: 1500 mg route of administration: Oral experiment type: SINGLE co-administered:		FLUCYTOSINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

T_1/2

Value	Dose	Co-administered	Analyte	Population
8.11 h EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/20038612	1500 mg single, oral dose: 1500 mg route of administration: Oral experiment type: SINGLE co-administered:		FLUCYTOSINE plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

F_unbound

Value	Dose	Co-administered	Analyte	Population
96.6% DRUG LABEL https://nctr-crs.fda.gov/fdalabel/services/spl/set-ids/5721b46a-4a9f-46c2-8804-a9bad4d5f80a/spl-doc?hl=flucytosine			FLUCYTOSINE plasma	Homo sapiens population: UNKNOWN age: UNKNOWN sex: UNKNOWN food status: UNKNOWN

Doses

Dose	Population	Adverse events
150 mg/kg 1 times / day multiple, oral (total daily dose) Recommended Dose: 150 mg/kg, 1 times / day Route: oral Route: multiple Dose: 150 mg/kg, 1 times / day Co-administed with:: fluconazole, p.o(400 mg/d) Sources: https://pubmed.ncbi.nlm.nih.gov/7803641 Page: p.743	unhealthy, 34 n = 32 Health Status: unhealthy Condition: Cryptococcal meningitis Age Group: 34 Sex: M Population Size: 32 Sources: https://pubmed.ncbi.nlm.nih.gov/7803641 Page: p.743	Disc. AE: Vomiting, Nausea... AEs leading to discontinuation/dose reduction: Vomiting (9.4%) Nausea (9.4%) Diarrhea (6.25%) Granulocytopenia (6.25%) Thrombocytopenia (3.1%) Rash (3.1%) Sources: https://pubmed.ncbi.nlm.nih.gov/7803641 Page: p.743
150 mg/kg 4 times / day multiple, oral (total daily dose\|max) Recommended Dose: 150 mg/kg, 4 times / day Route: oral Route: multiple Dose: 150 mg/kg, 4 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017001s027lbl.pdf	unhealthy Health Status: unhealthy Condition: Infections caused by susceptible strains of Candida and/or Cryptococcus Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017001s027lbl.pdf	Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2006/017001s027lbl.pdf

AEs

AE	Significance	Dose	Population
Rash	3.1% Disc. AE	150 mg/kg 1 times / day multiple, oral (total daily dose) Recommended Dose: 150 mg/kg, 1 times / day Route: oral Route: multiple Dose: 150 mg/kg, 1 times / day Co-administed with:: fluconazole, p.o(400 mg/d) Sources: https://pubmed.ncbi.nlm.nih.gov/7803641 Page: p.743	unhealthy, 34 n = 32 Health Status: unhealthy Condition: Cryptococcal meningitis Age Group: 34 Sex: M Population Size: 32 Sources: https://pubmed.ncbi.nlm.nih.gov/7803641 Page: p.743
Thrombocytopenia	3.1% Disc. AE	150 mg/kg 1 times / day multiple, oral (total daily dose) Recommended Dose: 150 mg/kg, 1 times / day Route: oral Route: multiple Dose: 150 mg/kg, 1 times / day Co-administed with:: fluconazole, p.o(400 mg/d) Sources: https://pubmed.ncbi.nlm.nih.gov/7803641 Page: p.743	unhealthy, 34 n = 32 Health Status: unhealthy Condition: Cryptococcal meningitis Age Group: 34 Sex: M Population Size: 32 Sources: https://pubmed.ncbi.nlm.nih.gov/7803641 Page: p.743
Diarrhea	6.25% Disc. AE	150 mg/kg 1 times / day multiple, oral (total daily dose) Recommended Dose: 150 mg/kg, 1 times / day Route: oral Route: multiple Dose: 150 mg/kg, 1 times / day Co-administed with:: fluconazole, p.o(400 mg/d) Sources: https://pubmed.ncbi.nlm.nih.gov/7803641 Page: p.743	unhealthy, 34 n = 32 Health Status: unhealthy Condition: Cryptococcal meningitis Age Group: 34 Sex: M Population Size: 32 Sources: https://pubmed.ncbi.nlm.nih.gov/7803641 Page: p.743
Granulocytopenia	6.25% Disc. AE	150 mg/kg 1 times / day multiple, oral (total daily dose) Recommended Dose: 150 mg/kg, 1 times / day Route: oral Route: multiple Dose: 150 mg/kg, 1 times / day Co-administed with:: fluconazole, p.o(400 mg/d) Sources: https://pubmed.ncbi.nlm.nih.gov/7803641 Page: p.743	unhealthy, 34 n = 32 Health Status: unhealthy Condition: Cryptococcal meningitis Age Group: 34 Sex: M Population Size: 32 Sources: https://pubmed.ncbi.nlm.nih.gov/7803641 Page: p.743
Nausea	9.4% Disc. AE	150 mg/kg 1 times / day multiple, oral (total daily dose) Recommended Dose: 150 mg/kg, 1 times / day Route: oral Route: multiple Dose: 150 mg/kg, 1 times / day Co-administed with:: fluconazole, p.o(400 mg/d) Sources: https://pubmed.ncbi.nlm.nih.gov/7803641 Page: p.743	unhealthy, 34 n = 32 Health Status: unhealthy Condition: Cryptococcal meningitis Age Group: 34 Sex: M Population Size: 32 Sources: https://pubmed.ncbi.nlm.nih.gov/7803641 Page: p.743
Vomiting	9.4% Disc. AE	150 mg/kg 1 times / day multiple, oral (total daily dose) Recommended Dose: 150 mg/kg, 1 times / day Route: oral Route: multiple Dose: 150 mg/kg, 1 times / day Co-administed with:: fluconazole, p.o(400 mg/d) Sources: https://pubmed.ncbi.nlm.nih.gov/7803641 Page: p.743	unhealthy, 34 n = 32 Health Status: unhealthy Condition: Cryptococcal meningitis Age Group: 34 Sex: M Population Size: 32 Sources: https://pubmed.ncbi.nlm.nih.gov/7803641 Page: p.743

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:5100	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:5100
ChemicalBook	CB6744939	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB6744939
MolPort	MolPort-000-155-561	https://www.molport.com/shop/molecule-link/MolPort-000-155-561
MolPort	MolPort-001-774-493	https://www.molport.com/shop/molecule-link/MolPort-001-774-493
MolPort	MolPort-002-317-353	https://www.molport.com/shop/molecule-link/MolPort-002-317-353
Selleck Chemicals	Flucytosine(Ancobon)	http://www.selleckchem.com/products/Flucytosine(Ancobon).html
ZINC	ZINC000000896546	http://zinc15.docking.org/substances/ZINC000000896546
eMolecules	511893	https://www.emolecules.com/cgi-bin/more?vid=511893
eMolecules	538448	https://www.emolecules.com/cgi-bin/more?vid=538448
eMolecules	736052	https://www.emolecules.com/cgi-bin/more?vid=736052
eMolecules	914155	https://www.emolecules.com/cgi-bin/more?vid=914155

PubMed

Title	Date	PubMed
Synergistic effects of low doses of histatin 5 and its analogues on amphotericin B anti-mycotic activity.	2000 Aug	11204768
Comparison of the Etest and microdilution method for antifungal susceptibility testing of Cryptococcus neoformans to four antifungal agents.	2000 Dec	11102421
[Mycosis in kidney transplant patients].	2001	11704745
Hypoxia and oxidative stress. Tumour hypoxia--therapeutic considerations.	2001	11597323
Vaginal mucormycosis: a case report.	2001	11495552
In vitro antifungal activities of voriconazole and reference agents as determined by NCCLS methods: review of the literature.	2001	11469757
Impact of endpoint definition on the outcome of antifungal susceptibility tests with Candida species: 24- versus 48-h incubation and 50 versus 80% reduction in growth.	2001	11398639
Systemic Candida infection in University hospital 1997-1999: the distribution of Candida biotypes and antifungal susceptibility patterns.	2001	11307597
Electrophoretic karyotyping and antifungal susceptibility patterns of Candida parapsilosis clinical isolates causing deep and superficial fungal infections.	2001	11307593
Imaging biochemistry: applications to breast cancer.	2001	11250743
Flucytosine primary resistance in Candida species and Cryptococcus neoformans.	2001 Apr	11399020
Simultaneous determination of flucytosine and fluorouracil in human plasma by high-performance liquid chromatography.	2001 Apr	11268048
Candida dubliniensis at a cancer center.	2001 Apr 1	11264031
Treatment of acute cryptococcal disease.	2001 Aug	11584993
A phase I trial of genetically modified Salmonella typhimurium expressing cytosine deaminase (TAPET-CD, VNP20029) administered by intratumoral injection in combination with 5-fluorocytosine for patients with advanced or metastatic cancer. Protocol no: CL-017. Version: April 9, 2001.	2001 Aug 10	11529249
Carcinoembryonic antigen-specific suicide gene therapy of cytosine deaminase/5-fluorocytosine enhanced by the cre/loxP system in the orthotopic gastric carcinoma model.	2001 Aug 15	11507067
Phenotypic characterization of Microsporum canis isolated from cats and dogs.	2001 Dec	11820261
Candida lusitaniae catheter-related sepsis.	2001 Dec	11793623
Phaeohyphomycosis due to Cladosporium cladosporioides.	2001 Feb	11270401
In vitro activity of a new echinocandin, LY303366, and comparison with fluconazole, flucytosine and amphotericin B against Candida species.	2001 Jan	11284937
Candida glabrata infection after total hip arthroplasty.	2001 Jan	11243760
Usefulness of repeated direct intratumoral gene transfer using hemagglutinating virus of Japan-liposome method for cytosine deaminase suicide gene therapy.	2001 Jan 1	11196152
Multimodality therapy with a replication-conditional herpes simplex virus 1 mutant that expresses yeast cytosine deaminase for intratumoral conversion of 5-fluorocytosine to 5-fluorouracil.	2001 Jul 15	11454690
Discontinuation of secondary prophylaxis against cryptococcosis in patients with AIDS receiving highly active antiretroviral therapy.	2001 Jul 27	11504971
In vitro susceptibility pattern of Sporothrix schenckii strains isolated from three centers in India.	2001 Jun	11816955
[In vitro antifungal susceptibility of dematiaceous filamentous fungi using the E-test].	2001 Jun	11704774
The mechanism of DNA cytosine-5 methylation. Kinetic and mutational dissection of Hhai methyltransferase.	2001 Jun 15	11283006
[Tenosynovitis caused by Cryptococcus neoformans in a patient with AIDS].	2001 Jun-Jul	11440675
[Antifungal susceptibility of emerging yeast pathogens].	2001 Jun-Jul	11440661
Stereospecific synthesis and biological evaluations of beta-L-pentofuranonucleoside derivatives of 5-fluorouracil and 5-fluorocytosine.	2001 May	11451533
Antifungal susceptibility testing and the correlation with clinical outcome in neonatal candidemia.	2001 May	11414524
Interactions of posaconazole and flucytosine against Cryptococcus neoformans.	2001 May	11302795
Therapy for fungal infections in leukemia.	2001 May	11296129
Pharmacotherapy of fungal eye infections.	2001 Nov	11825321
The echinocandins, first novel class of antifungals in two decades: will they live up to their promise?	2001 Nov	11770362
Case report. Mycotic arteritis due to Aspergillus fumigatus in a diabetic with retrobulbar aspergillosis and mycotic meningitis.	2001 Nov	11766108
Cytometric approach for a rapid evaluation of susceptibility of Candida strains to antifungals.	2001 Nov	11737085
Crystallization and preliminary X-ray analysis of bacterial cytosine deaminase.	2001 Nov	11679731
Effect of the growth medium on the in vitro antifungal activity of micafungin (FK-463) against clinical isolates of Candida dubliniensis.	2001 Nov	11679561
Development of azole resistance during fluconazole maintenance therapy for AIDS-associated cryptococcal disease.	2001 Nov 23	11698718
Enantiomeric synthesis of D- and L-cyclopentenyl nucleosides and their antiviral activity against HIV and West Nile virus.	2001 Nov 8	11689085
Sertaconazole: in-vitro antifungal activity against vaginal and other superficial yeast isolates.	2001 Oct	11760221
Cryptococcus neoformans infection in a cohort of Italian AIDS patients: natural history, early prognostic parameters, and autopsy findings.	2001 Oct	11757972
Sensitization of prostate cancer cell lines to 5-fluorocytosine induced by adenoviral vector carrying a CD transcription unit.	2001 Sep	11780394
Successful treatment of cryptococcal osteomyelitis and paraspinous abscess with fluconazole and flucytosine.	2001 Sep	11592758
Neonatal candidosis: clinical picture, management controversies and consensus, and new therapeutic options.	2002 Feb	11801585
Synthesis and biological activity of the new 5-fluorocytosine derivatives, 5'-deoxy-N-alkyloxycarbonyl-5-fluorocytosine-5'-carboxylic acid.	2002 Feb 11	11814824
Quantitation of cytosine deaminase mRNA by real-time reverse transcription polymerase chain reaction: a sensitive method for assessing 5-fluorocytosine toxicity in vitro.	2002 Feb 15	11814289
Negative selection of Plasmodium falciparum reveals targeted gene deletion by double crossover recombination.	2002 Jan	11796125
The structure of Escherichia coli cytosine deaminase.	2002 Jan 25	11812140

Patents

Sample Use Guides

In Vivo Use Guide

The usual dosage is 50 to 150 mg/kg/day administered in divided doses at 6- hour intervals.

Route of Administration: Oral

In Vitro Use Guide

MIC ≤4 ug/ml for susceptible pathogen

Name

Type

Language

FLUCYTOSINE

Official Name

English

5-FLUOROCYTOSINE [WHO-IP]

Common Name

English

RO-29915

Code

English

RO 2-9915

Code

English

ANCOBON

Brand Name

English

FLUCYTOSINE [WHO-IP]

Common Name

English

5-Fluorocytosine

Systematic Name

English

FLUCYTOSINE [USP IMPURITY]

Common Name

English

FLUOROCYTOSINE

Systematic Name

English

FLUCYTOSINE [MI]

Common Name

English

NSC-103805

Code

English

RO-2-9915

Code

English

FLUCYTOSINE [HSDB]

Common Name

English

FLUCYTOSINE [USAN]

Common Name

English

Flucytosine [WHO-DD]

Common Name

English

FLUCYTOSINE [ORANGE BOOK]

Common Name

English

CYTOSINE, 5-FLUORO-

Systematic Name

English

4-AMINO-5-FLUOROPYRIMIDIN-2(1H)-ONE [WHO-IP]

Systematic Name

English

FLUCYTOSINE [EP MONOGRAPH]

Common Name

English

FLUCYTOSINE [MART.]

Common Name

English

FLUCYTOSINE [USP-RS]

Common Name

English

FLUCYTOSINE [USP MONOGRAPH]

Common Name

English

FLUCYTOSINE [JAN]

Common Name

English

EMTRICITABINE IMPURITY E [WHO-IP]

Common Name

English

FLUCYTOSINUM [WHO-IP LATIN]

Common Name

English

flucytosine [INN]

Common Name

English

Classification Tree Code System Code

NCI_THESAURUS

C1557