5-Fluorouracil Flucytosine

With the aid of cytosine permease, flucytosine reaches the fungal cell where it is converted by cytosine deaminase into 5-fluorouracil [51-21-8]. Cytosine deaminase is not present in the host, which explains the low toxicity of 5-FC. 5-Fluorouracil is then phosphorylated and incorporated into RNA and may also be converted into 5-fluorodeoxyuridine monophosphate, which is a potent and specific inhibitor of thymidylate synthetase. As a result, no more thymidine nucleotides are formed, which in turn leads to a disturbance of the DNA-synthesis. These effects produce an inhibition of the protein synthesis and cell repHcation (1,23,24). 5-Fluorouracil caimot be used as an antimycotic. It is poorly absorbed by the fungus to begin with and is also toxic for mammalian cells. 

The preparation of 5-fluorouracil is given under "Fluorouracil." As described in U.S. Patent 3,040,026, 5-fluorouracil is then subjected to the following steps to give flucytosine. 

Fig. 5.20 Imidazoles (A-F) A, metronidazole B, clotrimazole C, miconazole D, econazole E, ketoconazole F, fluconazole G, flucytosine H, 5-fluorouracil I, terbinafme J, tolnaftate.

Diphenhydramine hydrochloride, 3,173 Diphenoxylate hydrochloride, 7,149 Disulflram, 4, 168 Dobutamine hydrochloride, 8,139 Droperidol, 7,171 Echothiophate iodide, 3,233 Epinephrine, 7, 193 Ergotamine tartrate, 6,113 Erythromycin, 8,139 Erythromycin estolate, 1, 101 2, 573 Estradiol valerate, 4,192 Ethambutol hydrochloride, 7,231 Ethynodiol diacetate, 3,253 Fenoprofen calcium, 6,161 Flucytosine, 5,115 Fludrocortisone acetate, 3, 281 Fluorouracil, 2,221 Fluoxymesterone, 7,251 Fluphenazine enanthate, 2, 245 4,523 Fluphenazine hydrochloride, 2,263 4,518 Gluthethimide,5,139 Gramicidin, 8,179 Griseofulvin, 8,219 Halcinonide, 8,251 Halothane, 1, 119 2,573 Hexetidine, 7,277 Hydralazine hydrochloride, 8,283 Hydroflumethiazide, 7,297 Hydroxyprogesterone caproate, 4,209 Hydroxyzine dihydrochloride, 7,319 Iodipamide, 3,333 Isocarboxazid, 2, 295... 

Flucytosine is converted in Candida fungi to 5-fluorouracil by the action of a specific cytosine deaminase. As an antimetabolite, this compound disrupts DNA and RNA synthesis (p. 298), resulting in a fungicidal effect Given orally, flucytosine is rapidly absorbed. It is well tolerated and often combined with amphotericin B to allow dose reduction of the lattet... 

Flucytosine Flucytosine, 5-fluorocytosine (35.4.4), is synthesized from fluorouracil (30.1.3.3). Fluorouracil is reacted with phosphorous oxychloride in dimethylaniline to make 2,4-dichloro-5-fluoropyrimidine (35.4.2), which is reacted with ammonia to make a product substituted with chlorine at the fourth position of the pyrimidine ring—4-amino-2-chloro-5-fluoropyrimidine (35.4.3). Hydrolysis of the chlorovinyl fragment of this compound in a solution of hydrochloric acid gives the desired flucytosine [52-55]. 

Flucytosine is a fluorinated derivative of pyrimidine. Its spectrum of activity is narrower than that of amphotericin B. However, it exhibits a synergetic effect when used in combination with amphotericin B. In sensitive fungi, flucytosine is transformed into 5-fluorouracil, which in turn is turned into 5-fluorodeoxyuracilic acid, an inhibitor of thymidylate synthetase, and correspondingly, DNA synthesis. 5-Fluorouracil triphosphate, which causes the formation of defective RNA, may also be involved in this process. The mechanism is highly selective because mammahan cells are not able to turn a large amount of flucytosine into 5-fluorouracil. 

Flucytosine is an oral antifungal pro-drug. It has to be enzymatically deaminated by the fungi to the active metabolite, fluorouracil. Fluorouracil inhibits thymidylate synthetase and DNA synthesis. Its indications are treatment of cryptococcal meningitis and serious systemic candidiasis. Resistance develops rapidly, due to altered drug-permeability. For this reason Amphotericin B and flucytosine are often given in combination as they have synergistic effects. 

Flucytosine is converted into the anti metabolite 5-fluorouracil that inhibits thymidilate synthetase, thereby disrupting DNA synthesis. It also interferes with protein synthesis by incorporation of fluorouracil into RNA in place of uracil. Although active against most Candida species, its spectrum of antifungal activity, overall, is narrow. Since resistance can develop rapidly it is usually coadministered with another agent and its main value is that it facilitates a reduction in the dose (and, presumably, the toxic effect) of amphotericin when co-prescribed in this way. The main adverse effects are marrow aplasia and hepatotoxicity. 

Flucytosine (5-FC) was discovered in 1957 during a search for novel antineoplastic agents. Though devoid of anticancer properties, it became apparent that it was a potent antifungal agent. Flucytosine is a water-soluble pyrimidine analog related to the chemotherapeutic agent fluorouracil (5-FU). Its spectrum of action is much narrower than that of amphotericin B. 

Mechanism of Action. Flucytosine is incorporated into susceptible fungi, where it undergoes enzymatic conversion to fluorouracil,7 which acts as an antimetabolite during RNA synthesis in the fungus. Fluorouracil is incorporated into RNA chains but acts as a false nucleic acid. This event ultimately impairs protein synthesis, thus disrupting the normal function of the fungus. 

Flucytosine (Ancobon) possesses clinically useful activity against Cryptococcus neoformans, Candida species, Torulopsis glabrata, and the agents of chromomycosis. Susceptible fungi deam-inate flucytosine to 5-fluorouracil, which becomes an antimetabolite. Flucytosine, which is excreted by the kidney, should be used cautiously in the setting of renal impairment. Flucytosine is a bone marrow depressant. Flucytosine is used in combination with amphotericin B. 

Pharmacokinetics Flucytosine is well absorbed by the oral route, distributes throughout the body water, and penetrates well into cerebrospinal fluid (CSF). 5-Fluorouracil is detectable in patients and probably is due to metabolism of 5-FC by intestinal bacteria. Excretion of both the parent drug and its metabolites is by glomerular filtration, and the dose must be adjusted in patients with compromised renal function. 

Biondi L, Nairn JC. Stability of 5-fluorouracil and flucytosine in parenteral solutions. Can J Hosp Pharm 1986 39 60-63,66. 

Flucytosine (5-fluorocytosine) is metabolised in the fungal cell to 5-fluorouracil which inhibits nucleic acid synthesis. It is weU absorbed from the gut, penetrates effectively into tissues and almost all is excreted unchanged in the urine (t) 4 h). The dose should be reduced for patients with impaired renal function, and the plasma concentration should be monitored. The drug is well tolerated when renal function is normal. Candida albicans rapidly becomes resistant to flucytosine which ought not to be used alone it may be combined with amphotericin (see Table 14.2) but this increases the risk of adverse effects (leucopenia, thrombocytopenia, enterocolitis) and it is reserved for serious infections where the risk-benefit balance is favourable (e.g. Cryptococcus neoformans meningitis). 

Flucytosine is an antimetaboUte of the fluoropyrimidme type. The principle of selectivity of flucytosine for the fungal cell is dual it depends on an enzyme in order to penetrate the cell (fungal cytosine permease) and a fungal enzyme that deaminates flucytosine to the active antimetabolite 5-fluorouracil, which is metabolized to 5-fluor-ouridine. Replacement of 5-fluorouracil in RNA results in the disruption of protein sjmthesis in the fungus. Flucytosine has selective activity against pathogenic... 

The mechanism of toxicity of flucytosine is not fully understood. Conversion of flucytosine to certain metabolites, in particular 5-fluorouracil, in the liver or by the intestinal microflora after oral administration has been proposed. Toxicity may also occur through impurities in the raw material and the formation of fluorouracil from flucytosine after sterilization and storage. 

Life-threatening fluorouracil-like cardiotoxicity has been attributed to flucytosine (15). 

In a pilot study in six patients receiving intravenous flucytosine, hematotoxicity was monitored by measuring platelet and leukocyte counts flucytosine and 5-fluorouracil serum concentrations were measured using HPLC (19). The concentrations of 5-fluorouracil in the 34 available serum samples were below the limit of quantification (0.05 pg/ml), but flucytosine was detectable in all samples and the 5-fluorouracil metabolite, a-fluoro-P-alanine (FBAL), was detected at low concentrations in several samples. One patient developed thrombocytopenia (50 X 10 /1) during therapy, and one developed leukopenia (2.6 X 10 /1). The fact that 5-fluorouracil was not detected... 

Enterocolitis, usually sparing the rectosigmoid, has been described in some cases (21). This type of flucytosine toxicity may be associated with deamination of flucytosine to 5-fluorouracil in the gut (1). Potentially fatal ulcerative colitis has been suspected in a few patients however, in most cases there were no diagnostic data to back up the diagnosis. 

Flucytosine is teratogenic in rats, and its close chemical relation to antimetabolites plus the fact that 5-fluorouracil is a metabolite make it inadvisable to administer flucytosine during pregnancy or to fertile women taking no contraceptive precautions. 

Flucytosine is a fluorinated pyrimidine that is transported across the fungal cell wall by a permease, where it is deaminated to the cytotoxic principal fluorouracil. Some fungi may lack the permease and are resistant to the drug and its clinical use is usually restricted to treating Candida spp. infection, although even here resistance may arise. It is synergistic with amphotericin B and... 

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