Conversion of 5-fluorocytosine to 5-fluorouracil by human intestinal microflora

Abstract

The mechanism of toxicity from 5-fluorocytosine chemotherapy is unclear. However, recent evidence suggests that the generation of 5-fluorouracil by a host may play an important role in the development of this toxicity. Using an in vitro semicontinuous culture system to mimic the intestinal microflora, we examined the capacity of this complex microbial community to convert 5-fluorocytosine to 5-fluorouracil. The system was dosed initially and after 2 weeks of chronic exposure to 5-fluorocytosine with radiolabeled 5-fluorocytosine. No detectable production of 5-fluorouracil was observed up to 8 h after the acute dose; however, at 24 h and at all time points thereafter, increasing levels of 5-fluorouracil were detected for 4 days. The chronic dose resulted in an increased rate of 5-fluorouracil production without the 8-h lag time. These findings suggest that the enzyme or enzymes responsible for the deamination of 5-fluorocytosine to 5-fluorouracil by the intestinal microflora can be induced by chronic exposure to 5-fluorocytosine and that this conversion may provide a mechanism through which 5-fluorocytosine toxicity is manifested.

Gut Microbiota-Mediated Drug-Antibiotic Interactions

“…1G) (Harris et al, 1986;Vermes et al, 2003). Consistent with this, when flucytosine was given to patients receiving antimicrobial agents, the level of 5-fluorouracil production decreased (Vermes et al, 2003).…”

An in vitro Study on the Active Conversion of Flucytosine to Fluorouracil by Microorganisms in the Human Intestinal Microflora

“…Several studies have pointed out that at 5FC levels exceeding 100 mg/l the risk of toxicity is increased [8,[16][17][18][19][20]. Although the mechanisms of toxicity of this antifungal drug are still not fully understood, it has been postulated that conversion of 5FC to certain metabolites, especially to 5FU, is involved in the development of 5FC-associated toxicity [21][22][23]. Although reports in the literature are scarce [11,24,25], 5FU and 5FU catabolites have been detected in urine and serum of 5FC-treated patients and it has been documented that 5FU can cause bone marrow depression as seen with 5FC therapy [21,26,27].…”

Oral versus Intravenous Flucytosine in Patients with Human Immunodeficiency Virus-Associated Cryptococcal Meningitis

“…Human cells lack the enzyme cytosine deaminase and are unable to convert 5FC into 5FU. However, the human intestinal microflora has been shown to be capable of converting 5FC into 5FU in vitro (8,10,17), and 5FU, at concentrations known to be associated with bone marrow depression, has been measured in the plasma of patients treated with oral 5FC (6). If intestinal bacteria do play a role in conversion of 5FC to 5FU in patients, then oral administration of 5FC might be associated with increased 5FU concentrations and more side effects than intravenous (i.v.)…”