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Fluorocytosine

Overview Mechanism of action and resistance Pharmacokinetic and dosage Toxicity and side effects References
Fluorocytosine
Fluorocytosine
CAS No.
2022-85-7
Chemical Name:
Fluorocytosine
Synonyms
5-FC;ancobon;ancotil;ALCOBON;ro2-9915;FLUCYTOSIN;FLUCYSTINE;FLUCYTOSINE;fluocytosine;5-FLUCYTOSINE
CBNumber:
CB6744939
Molecular Formula:
C4H4FN3O
Formula Weight:
129.09
MOL File:
2022-85-7.mol

Fluorocytosine Properties

Melting point:
298-300 °C (dec.)(lit.)
Density 
1.3990 (estimate)
storage temp. 
2-8°C
form 
Crystalline Powder
pka
3.26(at 25℃)
color 
White to almost white
Water Solubility 
1.5g/100mL (25 ºC)
Sensitive 
Light Sensitive
Merck 
14,4125
BRN 
127285
Stability:
Light Sensitive
InChIKey
XRECTZIEBJDKEO-UHFFFAOYSA-N
CAS DataBase Reference
2022-85-7(CAS DataBase Reference)
SAFETY
  • Risk and Safety Statements
  • Hazard and Precautionary Statements (GHS)
Hazard Codes  Xn,T,Xi
Risk Statements  40-36/37/38-63
Safety Statements  22-24/25-45-36/37-36/37/39-27-26
WGK Germany  2
RTECS  HA6040000
10-23
Hazard Note  Toxic/Light Sensitive
HazardClass  IRRITANT, LIGHT SENSITIVE
Hazardous Substances Data 2022-85-7(Hazardous Substances Data)
Toxicity LD50 in mice (mg/kg): >2000 orally and s.c.; 1190 i.p.; 500 i.v. (Grunberg, 1963)
Symbol(GHS):
Signal word: Warning
Hazard statements:
Code Hazard statements Hazard class Category Signal word Pictogram P-Codes
H341 Suspected of causing genetic defects Germ cell mutagenicity Category 2 Warning P201,P202, P281, P308+P313, P405,P501
H361 Suspected of damaging fertility or the unborn child Reproductive toxicity Category 2 Warning P201, P202, P281, P308+P313, P405,P501
Precautionary statements:
P201 Obtain special instructions before use.
P202 Do not handle until all safety precautions have been read and understood.
P280 Wear protective gloves/protective clothing/eye protection/face protection.
P281 Use personal protective equipment as required.
P308+P313 IF exposed or concerned: Get medical advice/attention.
P405 Store locked up.

Fluorocytosine price More Price(15)

Manufacturer Product number Product description CAS number Packaging Price Updated Buy
Sigma-Aldrich F0175000 Flucytosine European Pharmacopoeia (EP) Reference Standard 2022-85-7 1EA $168 2017-11-08 Buy
Sigma-Aldrich 1272000 Flucytosine United States Pharmacopeia (USP) Reference Standard 2022-85-7 200mg $348 2018-11-13 Buy
TCI Chemical F0321 5-Fluorocytosine >98.0%(HPLC)(T) 2022-85-7 1g $38 2017-12-01 Buy
TCI Chemical F0321 5-Fluorocytosine >98.0%(HPLC)(T) 2022-85-7 5g $114 2017-12-01 Buy
Alfa Aesar L16496 5-Fluorocytosine, 98+% 2022-85-7 250mg $31.3 2018-11-13 Buy

Fluorocytosine Chemical Properties,Uses,Production

Overview

A fluorinated pyrimidine, 5-flucytosine (fluorocytosine; 5-FC, Fig. 1), was initially developed as a potential anti-cancer agent but it was not sufficiently effective in the field of cancer chemotherapy[1]. Later, 5-FC proved to be active in experimental candidiasis and cryptococcosis in mice[2] and was used to treat human infections[3]. In addition to its activity against Candida and Cryptococcus, 5-FC also has an inhibitory activity against fungi causing chromoblastomycosis[4]; however, it is ineffective against infections caused by filamentous fungi. 5-FC has a high prevalence of primary resistance in many fungal species. Due to this primary resistance, 5-FC is used mainly in combination with other antifungals (primarily amphotericin B, AmB) and more recently it has been investigated in combination with other agents including fluconazole (FLU), ketoconazole (KTZ), itraconazole (ITRA), voriconazole (VORI) and echinocandins (e.g., micafungin, MICA and caspofungin, CAS). It is used only rarely as a single agent.
Flucytosine (5-FC) is a synthetic antimycotic compound, first synthesized in 1957. It has no intrinsic antifungal capacity, but after it has been taken up by susceptible fungal cells, it is converted into 5-fluorouracil (5-FU), which is further converted to metabolites that inhibit fungal RNA and DNA synthesis. Monotherapy with 5-FC is limited because of the frequent development of resistance. In combination with amphotericin B, 5-FC can be used to treat severe systemic mycoses, such as cryptococcosis, candidosis, chromoblastomycosis and aspergillosis.

Figure 1 the chemical structure of Fluorocytosine ;

Mechanism of action and resistance

5-FC is most active against yeasts, including Candida, Torulopsis and Cryptococcus spp., and against the dematiaceous fungi causing chromomycosis (Phialophora and Cladosporium spp.) and Aspergillus spp.[5] The MICs of 5-FC vary from 0.1 to 0.25 mg/L for these fungal species.
In Emmonsia crescens, Emmonsia parva, Madurella mycetomatis, Madurella grisea, Pyrenochaeta romeroi, Cephalosporium spp., Sporothrix schenckii and Blastomyces dermatitidis, MICs vary from 100 to 1000 mg/L.14 5-FC is also active against some protozoa, including Acanthamoeba culbertsoni both in vitro and in vivo and Leishmania spp. in patients.[5]
Antimycotic activity of 5-FC results from its rapid conversion into 5-fluorouracil (5-FU) by the enzyme cytosine deaminase, within susceptible fungal cells. There are two mechanisms involved by which 5-fluorouracil exerts its antifungal activity. The first mechanism includes the conversion of 5-fluorouracil through 5-fluorouridine monophosphate (FUMP) and 5-fluorouridine diphosphate (FUDP) into 5-fluorouridine triphosphate (FUTP)[6]. FUTP is further incorporated into fungal RNA in place of uridylic acid; this alters the amino- acylation of tRNA, disturbs the amino acid pool and inhibits protein synthesis[6]. The second mechanism is the metabolism of 5-FU into 5-fluorodeoxyuridine monophosphate (FdUMP) by uridine monophosphate pyrophosphorylase[6]. FdUMP is a potent inhibitor of thymidylate synthase, which is a key enzyme involved in DNA synthesis and nuclear division[7]. Thus, 5-FC acts by interfering with pyrimidine metabolism and protein synthesis in the fungal cell. These activity results in cell lysis and death.
The occurrence of resistance with the use of 5-FC has been widely described and precludes use of 5-FC as a single agent[8, 10] Two basic mechanisms of resistance can be distinguished: (i) certain mutations can result in a deficiency in the enzymes necessary for cellular transport and uptake of 5-FC or for its metabolism (i.e. cytosine permease, uridine monophosphate pyrophosphorylase or cytosine deaminase);[9,11] (ii) resistance may result from increased synthesis of pyrimidines, which compete with the fluorinated antimetabolites of 5-FC and thus diminish its antimycotic activity.[9] It has been shown that defective uridine monophosphate pyrophosphorylase is the most frequently occurring type of acquired 5-FC resistance in fungal cells.[12] Normark & Schönebeck have reported that two different phenotypes of 5-FC-resistant strains can be recognized:[10] strains of resistance phenotype class 1 are not affected by 5-FC at high concentrations (these are the totally (intrinsically) resistant strains), while those of class 2 are susceptible to 5-FC at low concentrations but, after long exposure to 5-FC (even at high concentrations) resistance develops (these are said to be partially resistant or to have acquired resistance). Development of resistance in the latter strains probably results from selection of non-susceptible mutants, leading to a secondary resistant population.[9]
The incidence of resistance to 5-FC varies between species.20 Up to 7–8% of intrinsically resistant strains are found among pretreatment isolates of C. albicans, unspeciated candida and Torulopsis glabrata. In C. neoformans the incidence of resistance is lower (1–2%), but in Candida spp. other than C. albicans it is 22%, because of the prevalence of generally less sensitive species such as Candida tropicalis and Candida krusei[13]. The exact incidence of primary 5-FC resistance is not clear. Different investigators report rates ranging between 8% and 44% for Candida spp[14]. Possible factors contributing to this wide range include the susceptibility methods used, local factors involving use of anti- fungal agents and differences in the prevalence of various Candida spp[14].

Pharmacokinetic and dosage

5-FC is absorbed very rapidly and almost completely: 76–89% is bioavailable after oral administration.[16] In patients with normal renal function, peak concentrations are attained in serum and other body fluids within 1–2 h.[15, 16]. 5-FC penetrates well into most body sites, including cerebrospinal, vitreous and peritoneal fluids, and into inflamed joints, because it is small and highly water-soluble and is not bound by serum proteins to a great extent[15-17]. 5-FC is principally eliminated by the kidneys and the plasma clearance of the drug is closely related to creatinine clearance[15, 17]. 5-FC is only minimally metabolized in the liver. Renal elimination is via glomerular filtration; no tubular resorption or secretion takes place. The half-life of 5-FC is c.3–4 h in patients with normal renal function, but can be extended up to 85 h in patients with severe renal insufficiency.[12, 16, 18] Renal insufficiency alters 5-FC pharmacokinetics since it slows absorption, prolongs serum half-life and decreases clearance[15]. The apparent volume of distribution of 5-FC approaches that of total body water and is not altered by renal failure.
Dosage must be adjusted in patients with renal impairment. Various recommendations have been made[15-18]. Daneshmend & Warnock have suggested the following guidelines for the administration of 5-FC to patients with renal insufficiency.[15]. In patients with a creatinine clearance of >40 mL/min, a standard dose of 37.5 mg/kg every 6 h should be used. If the creatinine clearance is between 20 and 40 mL/min, the recommended dose is 37.5 mg/kg every 12 h. In patients with a creatinine clearance of <20 mL/ minute, the dose of 5-FC should be 37.5 mg/kg once daily. Finally, if the creatinine clearance is <10 mL/min, frequent determinations of 5-FC concentration should be used as guidance for the frequency of dosing.

Toxicity and side effects

5-FC is known to have some relatively minor side effects, such as nausea, vomiting and diarrhoea, it also has more severe side effects, including hepatotoxicity and bone- marrow depression. Gastrointestinal side effects, the most common and least harmful side effects associated with 5-FC treatment, include nausea, diarrhoea and, occasionally, vomiting and diffuse abdominal pain. They occur in approximately 6% of patients treated with 5-FC[18]. Although these side effects are usually not severe; two cases of ulcerative colitis and bowel perforation have been reported[19]. Hepatotoxicity can occur during 5-FC treatment. In most cases it involves increases in serum concentrations of transaminases and alkaline phosphatase[20]. The incidence of hepatotoxicity is between 0 and 25%[20]. The most severe toxicity associated with 5-FC treatment are bone-marrow depression. There have been several reports of serious or life-threatening leucocytopenia, thrombocytopenia and/or pancytopenia[21-23]. The mechanism of toxicity of 5-FC is still not fully understood. It is likely that some of the side effects caused by 5-FC, for example hepatotoxicity and bone-marrow depression, are dose-dependent, although not all reports support this theory. Furthermore, it has been postulated that conversion of 5-FC to certain metabolites, especially 5-FU, could be one of the mechanisms of development of 5-FC-associated toxicity.

References

  1. Heidelberg C, Chaudhuri NK, Danneberg P et al. Fluorinated pyrimidines, a new class of tumour-inhibitory compounds. Nature 1957; 179(4561): 663–666
  2. Grunberg E, Titsworth E, Bennett M. Chemotherapeutic activity of 5-fluorocytosine. Antimicrob Agents Chemother 1963; 161:566–568
  3. Tassel D, Madoff MA. Treatment of Candida sepsis and Cryptococcus meningitis with 5-fluorocytosine. A new antifungal agent. JAMA 1968; 206(4): 830–832
  4. Benson JM, Nahata MC. Clinical use of systemic antifungal agents. Clin Pharm 1988; 7(6): 424–438
  5. Scholer, H. J. (1980). Flucytosine. In Antifungal Chemotherapy, (Speller, D. C. E., Ed.), pp. 35–106. Wiley, Chichester.
  6. Waldorf AR, Polak A. Mechanisms of action of 5-fluorocytosine. Antimicrob Agents Chemother 1983; 23(1):79–85
  7. Diasio RB, Bennett JE, Myers CE. Mode of action of 5-fluorocytosine. Biochem Pharmacol 1978; 27(5):703–707
  8. Polak, A. & Scholer, H. J. (1975). Mode of action of 5-fluoro- cytosine and mechanisms of resistance. Chemotherapy 21, 113–30.
  9. Polak, A. (1977). 5-Fluorocytosine—current status with special references to mode of action and drug resistance. Contributions to Microbiology and Immunology 4, 158–67.
  10. Normark, S. & Schönebeck, J. (1973). In vitro studies of 5-fluorocytosine resistance in Candida albicans and Torulopsis glabrata. Antimicrobial Agents and Chemotherapy 2, 114–21.
  11. Fasoli, M. & Kerridge, D. (1988). Isolation and characterization of fluoropyrimidine-resistant mutants in two Candida species. Annals of the New York Academy of Sciences 544, 260–3.
  12. Francis, P. & Walsh, T. J. (1992). Evolving role of flucytosine in immunocompromised patients: new insights into safety, pharmaco- kinetics, and antifungal therapy. Clinical Infectious Diseases 15, 1003–18.
  13. Medoff, G. & Kobayashi, G. S. (1980). Strategies in the treat- ment of systemic fungal infections. New England Journal of Medicine 302, 145–55.
  14. Armstrong, D. & Schmitt, H. J. (1990). Older drugs. In Chemotherapy for Fungal Diseases, (Ryley, J. F., Ed.), pp. 439–54. Springer-Verlag, Berlin.
  15. Daneshmend, T. K. & Warnock, D. W. (1983). Clinical pharmaco- kinetics of systemic antifungal drugs. Clinical Pharmacokinetics 8, 17–42.
  16. Cutler, R. E., Blair, A. D. & Kelly, M. R. (1978). Flucytosine kinetics in subjects with normal and impaired renal function. Clinical Pharmacology and Therapeutics 24, 333–42.
  17. Block, E. R., Bennett, J. E., Livoti, L. G., Klein, W. J., MacGre- gor, R. R. & Henderson, L. (1974). Flucytosine and amphotericin B: hemodialysis effects on the plasma concentration and clearance. Studies in man. Annals of Internal Medicine 80, 613–7.
  18. Schönebeck, J., Polak, A., Fernex, M. & Scholer, H. J. (1973). Pharmacokinetic studies on the oral antimycotic agent 5-fluoro- cytosine in individuals with normal and impaired kidney function. Chemotherapy 18, 321–36.
  19. Benson, J. M. & Nahata, M. C. (1988). Clinical use of systemic antifungal agents. Clinical Pharmacy 7, 424–38.
  20. Bennet, J. E. (1977). Flucytosine. Annals of Internal Medicine 86, 319–21.
  21. Kauffman, C. A. & Frame, P. T. (1977). Bone marrow toxicity associated with 5-fluorocytosine therapy. Antimicrobial Agents and Chemotherapy 11, 244–7.
  22. Schlegel, R. J., Bernier, G. M., Bellanti, J. A., Maybee, D. A., Osborne, G. B., Stewart, J. L. et al. (1970). Severe candidiasis associated with thymic dysplasia, IgA deficiency, and plasma antilymphocyte effects. Pediatrics 45, 926–36.
  23. Meyer, R. & Axelrod, J. L. (1974). Fatal aplastic anemia result- ing from flucytosine. Journal of the American Medical Association 228, 1573.

Chemical Properties

White Crystalline Solid

Uses

antidiabetic

Uses

antifungal and antimicrobial agent

Uses

5-FC is a toxic antifungal/antimicrobial agent

Definition

ChEBI: An organofluorine compound that is cytosine that is substituted at position 5 by a fluorine. A prodrug for the antifungal 5-fluorouracil, it is used for the treatment of systemic fungal infections.

brand name

Ancobon (Valeant).

Fluorocytosine Preparation Products And Raw materials

Raw materials

Preparation Products


Fluorocytosine Suppliers

Global( 421)Suppliers
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View Lastest Price from Fluorocytosine manufacturers

Image Release date Product Price Min. Order Purity Supply Ability Manufacturer
2018-08-16 Fluorocytosine
2022-85-7
US $7.00 / KG 1KG 99% 1000KG
2018-07-24 Fluorocytosine
2022-85-7
US $1000.00 / KG 1KG 98% 1ton

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