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

Vermes, A.

doi:10.1093/jac/46.2.171

Cited by 803Antifungal resistance and susceptibilityFungal Infections and StudiesPharmacogenetics and Drug Metabolism

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

Vermes, A.·2000·Journal of Antimicrobial Chemotherapy

DOI 10.1093/jac/46.2.171

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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.

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Resistance to 5-flucytosine rendered this drug obsolete against Candida in less than 20 years.
“For comparison, the antifungal drug 5-flucytosine was introduced several years later than AmB, but resistance rendered this drug obsolete against Candida in less than 20 years [10].”
From Fitness Trade-offs Restrict the Evolution of Resistance to Amphotericin B (2013) · cites this paper as [10]
Flucytosine inhibits thymidylate synthase and DNA synthesis, and its metabolite can be incorporated into RNA, affecting RNA and protein synthesis.
“This fluorinated nucleotide inhibits thymidylate synthase and thus interferes with DNA synthesis (Figure 1, [31]). The 5-fluorodeoxyuridine monophosphate can be further phosphorylated and incorporated to RNA, thus affecting RNA and protein synthesis (Figure 1, [32]).”
From CandidaInfections, Causes, Targets, and Resistance Mechanisms: Traditional and Alternative Antifungal Agents (2013) · cites this paper as [31]

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Authors: Vermes, A.
Affiliations: Amsterdam UMC Location University of Amsterdam (NL)
Corresponding author: Vermes, A.
Venue: Journal of Antimicrobial Chemotherapy
Publisher: Oxford University Press (OUP)
Published: 2000-08-01
Volume: 46
Issue: 2
Pages: 171-179
ISSN: 0305-7453 (ISSN-L)
1460-2091
DOI: 10.1093/jac/46.2.171
OpenAlex: W2108675611
Cited by: 803
References: 67
Citations by year: 2026: 42 · 2025: 41 · 2024: 59 · 2023: 44 · 2022: 43 · 2021: 51 · 2020: 40 · 2019: 38 · 2018: 30 · 2017: 44 · 2016: 37 · 2015: 36 · 2014: 44 · 2013: 24 · 2012: 33
FWCI: 9.68
Type: journal article
Language: en
Open access: closed
Locations: Journal of Antimicrobial Chemotherapy (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
Health Sciences › Medicine › Epidemiology › Fungal Infections and Studies
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords: 5-fluorocytosine, 5-fluorouracil, antifungal agents, systemic fungal infection, cryptococcosis, candidiasis, chromoblastomycosis, aspergillosis, drug resistance, hepatotoxicity, bone marrow depression, pharmacokinetics, renal dysfunction, drug interactions, nephrotoxic drugs, amphotericin B, glomerular filtration
MeSH terms: Animals, Antifungal Agents, Drug Interactions, Flucytosine, Fungi, Humans, Mycoses

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

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