Chemical formula: C₄H₄FN₃O Molecular mass: 129.093 g/mol PubChem compound: 3366
Flucytosine is a fluorinated pyrimidine derivative. It is an antimycotic agent exerting fungistatic and fungicidal activity by interfering with protein and DNA synthesis. Fungal cells absorb flucytosine selectively via cytosine permease. It is desaminated to 5-fluorouracil which is then incorporated into fungal RNA, leading to faulty protein biosynthesis. 5-Fluorouracil is also converted to fluorodeoxyuridine monophosphate by uracil phosphoribosyltransferase (UPRTase). Fluorodeoxyuridine interferes with the enzyme thymidylate synthase. Inhibition of thymidylate synthase subsequently causes disruption of DNA synthesis.
Two major mechanisms of resistance have been described:
Resistance may also result from increased synthesis of pyrimidines, which compete with the fluorinated antimetabolites of 5-FC and thus diminish its antimycotic activity. Other mechanisms of flucytosine resistance include the up-regulated expression of a vacuolar glutathione S-conjugate pump that pumps flucytosine out of cells as well as the induced expression of a multi-drug resistance gene that permeates flucytosine out of cells.
Most strains of C. albicans, C. dubliniensis, C. famata, C. glabrata, C. guilliermondi and C parapsilosis are initially susceptible to flucytosine. Most strains of C. krusei are intermediately susceptible, while resistance is common in C. lusitaniae. Intermediately susceptible or resistant strains are also not uncommon in C. tropicalis.
Resistance to C. neoformans is rare but around 30% of strains show intermediate susceptibility.
Secondary resistance may develop, in particular with flucytosine monotherapy. Strains initially susceptible to flucytosine may become resistant during therapy. It is thus recommended to estimate the susceptibility of the strains before and during therapy. Combination of flucytosine and other antimycotic agents such as amphotericin B and triazoles often result in a synergistic effect; the MIC value achieved with the combination is less than the MIC values of the individual substances.
Bioavailability after an oral dose of 2 g varies between individuals and ranges from 76–98%. Peak plasma concentrations are reached within 1–2 hours after oral administration but may be delayed in subjects with renal impairment to 4-6 hours. Food and antacids decrease the absorption rate, but the total extent absorbed is not relevantly affected.
Flucytosine is widely distributed in body tissues and fluids (including cerebrospinal fluid). The volume of distribution is between 0.5 and 1.0 l/kg.
Binding to plasma proteins is minimal (<5%). Typical maximum serum concentrations are between 30 and 50 ug/ml after oral intake or intravenous administration of 2 g flucytosine. Flucytosine concentrations in cerebrospinal fluid, saliva and peritoneal fluid are slightly lower.
Flucytosine crosses the human placenta. Accumulation of flucytosine in amniotic fluid has been observed.
The urinary concentrations of flucytosine may be up to 100 times higher than plasma concentrations, in patients with a normal renal function.
Only a small proportion of flucytosine is metabolised. Enteric bacteria may be responsible for some metabolism of flucytosine to 5-fluorouracil (5-FU). Additionally 5-FU is released from killed fungi cells. The 5-FU/5-FC ratio of plasma concentrations is low (4%).
The plasma half-life is 3-6 hours in patients with normal renal function but this value increases in renal failure (30-250 hours). Excretion is almost exclusively through glomerular filtration. About 90% of the dose administered is excreted unchanged in the urine.
Flucytosine is readily removed by haemodialysis. Elimination via peritoneal dialysis is possible
The limited data available on flucytosine pharmacokinetic properties in paediatric patients suggest that in children, especially neonates flucytosine half-life is longer than in adults (4 vs 7 h). One neonatal pharmacokinetic study demonstrated that flucytosine half-life was twice as that reported in adults, although peak concentrations were comparable. Additionally, the volume of distribution of flucytosine approximates the volume of total body water due to its high solubility. In a retrospective study of 391 paediatric patients, 65% of flucytosine trough concentrations exceeded the normal reference range.
In vitro investigations on mutagenic potential of flucytosine were negative.
No studies are available on the carcinogenic potential of flucytosine.
Flucytosine has been shown to be teratogenic and embryotoxic in rats when given in oral or parenteral doses of 40 mg/kg body weight per day onwards (240 mg/m² or 0.043 times the human daily dose).
The flucytosine metabolite 5-fluorouracil is genotoxic in mice and in vitro, embryotoxic and teratogenic in mice and rats, and is classified as possible human teratogen.
Malformations occurred (defects in the nervous system, palate, skeleton, tails, limbs) in several species (including rat and Syrian Golden hamsters). Embryotoxic effects (small foetus, resorption) are also observed in monkeys treated with 5-fluorouracil.
Both flucytosine and 5-fluorouracil cross the placenta.
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