Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions

Abstract

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. Recently, 5-FC has been combined with newer azole antifungal agents; it also plays an important role in a new approach to the treatment of cancer. The severe side effects of 5-FC include hepatotoxicity and bone-marrow depression. In most patients, these side effects are concentration dependent, predictable, possibly avoidable with close monitoring to maintain 5-FC concentrations at <100 mg/L, and reversible with drug discontinuation or reduction of dose. 5-FC is well absorbed after oral administration, penetrates into body tissues well and is excreted mainly by the kidneys. In renal failure, major dose adjustments have to be made. The most important drug interaction of 5-FC occurs with concomitant administration of 5-FC and nephrotoxic drugs, especially amphotericin B. Owing to the crucial role of glomerular filtration in 5-FC elimination, drugs that impair this mechanism will decrease the elimination of 5-FC and thus prolong its half-life.

Alteration of enzyme specificity by computational loop remodeling and design

“…We applied the method to altering the specificity of human guanine deaminase (hGDA) with the long-term goal of introducing cytosine deaminase activity into a human protein scaffold. A designed cytosine deaminase with a sequence close to that of a human protein would solve an important problem in suicide gene therapy (16)(17)(18) by providing prodrug-activating ability (19)(20)(21)(22) while retaining low immunogenicity, as described in the SI Text. We consider hGDA to be the best starting point for such an effort based on the complement of deaminases that exist in the human genome (23,24).…”

Identification of inhibitors of yeast-to-hyphae transition in Candida albicans by a reporter screening assay

“…In spite of the clinical application of four classes of antimycotics against systemic candidiasis, there have been continuous efforts to discover and develop new antimycotic compounds, as existing drugs may be associated with toxic side-effects or interactions with other therapeutics, high costs and resistance development (Gubbins and Amsden, 2005;Vermes et al, 2000). Beside the screening for compounds with fungicidal or fungistatic activity and the description of novel potential antimycotic therapeutics (reviewed by Calugi et al (2011)), the recent years also saw the development of novel approaches to the search for antifungal agents (for example BurgerKentischer et al, 2011;Lafleur et al, 2011).…”

Optimizing antifungal drug dosing and monitoring to avoid toxicity and improve outcomes in patients with haematological disorders

“…[136][137][138] Hepatotoxicity appears to be dose-dependent, occurring more frequently when peak 5-FC concentrations are above 100 mg/mL Bone marrow suppression…”

“…The incidence is dose-dependent (observed when levels are >100 mg/L) and influenced by comorbidities, pre-existing bone marrow suppression and disease 136 Toxicity data are taken from trials using doses expected to have a therapeutic effect on invasive fungal infections (i. The lipid formulations of amphotericin are less nephrotoxic than AmB-D. Three meta-analyses reported that these agents reduced the incidence of nephrotoxicity by 49-75% compared with AmB-D, although they are not significantly different from each other in terms of their potential to cause nephrotoxicity.…”