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

Vermes, András; Kuijper, Ed J.; Guchelaar, Henk‐Jan; Dankert, J.

doi:10.1159/000069784

Cited by 45 publications

(30 citation statements)

References 20 publications

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“…Such regimens, in turn, will modify the current treatment strategies that are based on conventional pathologic and pharmacokinetic parameters to take into account the interindividual perturbations in the gut microbiota and the gut ecosystem. These measures are especially true with the evidence of the symxenobiotic metabolism that involves both the host and the associated microbiota to biotransform drugs, including first-line therapies [9,44] (Table 3). As a consequence, microbiome-labile medications may be limited, or their dose readjusted, for certain populations or individuals harboring particular gut microbial community profiles.…”

Section: Impact Of Microbiome Variations On Drug Response and Toxicitymentioning

confidence: 99%

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Diet-Microbiota Interactions and their Implications for Healthy Living

2014

Health and the Gut

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The influence of resident gut microbes on xenobiotic metabolism has been investigated at different levels throughout the past five decades. However, with the advance in sequencing and pyrotagging technologies, addressing the influence of microbes on xenobiotics had to evolve from assessing direct metabolic effects on toxins and botanicals by conventional culture-based techniques to elucidating the role of community composition on drugs metabolic profiles through DNA sequence-based phylogeny and metagenomics. Following the completion of the Human Genome Project, the rapid, substantial growth of the Human Microbiome Project (HMP) opens new horizons for studying how microbiome compositional and functional variations affect drug action, fate, and toxicity (pharmacomicrobiomics), notably in the human gut. The HMP continues to characterize the microbial communities associated with the human gut, determine whether there is a common gut microbiome profile shared among healthy humans, and investigate the effect of its alterations on health. Here, we offer a glimpse into the known effects of the gut microbiota on xenobiotic metabolism, with emphasis on cases where microbiome variations lead to different therapeutic outcomes. We discuss a few examples representing how the microbiome interacts with human metabolic enzymes in the liver and intestine. In addition, we attempt to envisage a roadmap for the future implications of the HMP on therapeutics and personalized medicine.

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Section: Impact Of Microbiome Variations On Drug Response and Toxicitymentioning

confidence: 99%

“…Potentiate effect [44] Metronidazole {4173} Antibiotic: antifungal and antimicrobial (against anaerobic microbes)…”

Section: Glutathione Peroxidase 2 (Gpx2) Enzymementioning

confidence: 99%

Diet-Microbiota Interactions and their Implications for Healthy Living

2014

Health and the Gut

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“…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.)…”

mentioning

confidence: 99%

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

Brouwer

Kan

Johnson³

et al. 2007

Antimicrob Agents Chemother

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In a randomized controlled trial of amphotericin B-based therapy for human immunodeficiency virus (HIV)-associated cryptococcal meningitis in Thailand, we also compared the mycological efficacy, toxicity, and pharmacokinetics of oral versus intravenous flucytosine at 100 mg/kg of body weight/day for the initial 2 weeks. Half of 32 patients assigned to the two arms containing flucytosine were randomized to oral and half to intravenous flucytosine. Early fungicidal activity was determined from serial quantitative cultures of cerebrospinal fluid (CSF), and toxicity was assessed by clinical and laboratory monitoring. Flucytosine and fluorouracil concentrations in plasma and CSF were measured by high-performance liquid chromatography. No significant bone marrow or hepatotoxicity was seen, there was no detectable difference in bone marrow toxicity between patients on intravenous and those on oral formulation, and no patients discontinued treatment. In patients receiving intravenous flucytosine, the median 24-h area under the concentration-time curve was significantly higher than in the oral group. Despite this difference, there was no difference in early fungicidal activity between patients on intravenous compared with patients on oral flucytosine. The results suggest that either formulation can be used safely at this dosage in a developing country setting, without drug concentration monitoring. The bioavailability of the oral formulation may be reduced in late-stage HIV-infected patients in Thailand. Concentrations of flucytosine with intravenous formulation at 100 mg/kg/day may be in excess of those required for maximal fungicidal activity.Flucytosine (5FC) in combination with amphotericin B (AMB) is standard therapy for cryptococcal meningitis in the United States and Europe. 5FC is taken up by fungal cells by cytosine permease and converted into fluorouracil (5FU) by fungal cytosine deaminase. Further metabolism of 5FU leads to the formation of 5-fluorouridine triphosphate, which is incorporated into fungal RNA, and 5-fluorodeoxyuridine monophosphate, an inhibitor of thymidylate synthetase. This results in inhibition of protein and DNA synthesis in the fungal cell (19).Side effects of 5FC include nausea, vomiting, diarrhea, bone marrow depression, and hepatotoxicity. The latter two are thought to be due to effects of 5FU. 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.) administration of the drug. On the other hand, i.v. 5FC is more costly to administer in resource-poor settings and carries the added incon...

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“…Limited drug absorption was demonstrated after the presumed gastric emptying time, i.e., 2.5 h and beyond. Two potential explanations for the reduced absorption include a lower rate of drug release at alkaline pH values and/or the increased gut microbial conversion of 5FC to its metabolite, 5-fluorouracil (27). The HPLC method used in the current study demonstrated plasma 5FU concentrations below detectable levels.…”

Section: Discussionmentioning

confidence: 71%

“…The HPLC method used in the current study demonstrated plasma 5FU concentrations below detectable levels. However, 5FU is known to be poorly absorbed from the gastrointestinal tract (27). Hence, confirmation of gut microbial conversion may require the collection of feces for total drug recovery estimation in future studies.…”

Section: Discussionmentioning

confidence: 99%

Clinical Pharmacokinetics of Oral Controlled-Release 5-Fluorocytosine

Pai

Bruce

Felton

2010

Antimicrob Agents Chemother

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5-Fluorocytosine (5FC) is an oral antifungal that is currently used in combination with amphotericin B totreat Cryptococcus neoformans meningoencephalitis. The oral dosing of 5FC could be optimized by the use of a controlled-release (CR) formulation. The objective of the current study was to develop two prototype 5FC-CR formulations and evaluate the single-dose (1,500-mg) serum pharmacokinetic profiles of those formulations relative to the profile of the commercially available, immediate-release 5FC product (Ancobon) by the use of a phase 1, open-label, randomized, three-phase, crossover pharmacokinetic study design. Hydroxypropyl methylcellulose was utilized as the rate-controlling matrix to compound the 5FC-CR tablets. The two prototype 5FC-CR formulations demonstrated 80% release at 13.0 and 18.4 h, respectively, whereas the immediaterelease product demonstrated 80% release at 0.28 h, as determined in vitro by the United States Pharmacopeia apparatus 2 dissolution method. Five subjects completed all three phases of the study without any adverse events. The mean maximum concentration, the area under the curve from time zero to 24 h, and the area under the curve from time zero to infinity were approximately 50% lower (P < 0.01) with the 5FC-CR formulations than with the immediate-release 5FC product. However, no statistically significant differences in the minimum concentrations at 24 h were noted between the formulations. The gastric absorption profile of 5FC-CR was well predicted by in vitro dissolution. Future exploration of a gastroretentive 5FC-CR formulation could overcome the marked lack of bioequivalence observed in the present study.Cryptococcus neoformans is an opportunistic fungal pathogen that is associated with significant morbidity and mortality. A 27% mortality rate has been associated with Cryptococcus neoformans meningoencephalitis (CNME) among AIDS patients in South Africa (15). An induction antifungal regimen of amphotericin B (AMB) and 5-fluorocytosine (5FC) for 2 weeks, followed by long-term fluconazole (FLZ) maintenance therapy, is considered the standard of care for AIDS patients with CNME (20). While it is effective, the use of induction therapy has been too complex for implementation in developing countries (11). The use of FLZ monotherapy in AIDS patients with CNME has been utilized but is associated with treatment failure and the emergence of resistance (3, 18). Hence, access to a simple, easy-to-administer combination oral antifungal regimen could improve CNME-related outcomes in countries without sufficient resources. The use of oral 5FC and FLZ combination regimens have demonstrated promising clinical results (4,8,10,14,16).However, currently recommended 5FC dosing regimens may not be optimal on the basis of pharmacokinetic (PK) and pharmacodynamic (PD) principles (7). For example, administration of 5FC at 25 mg/kg of body weight by mouth every 6 h yields steady-state maximum plasma concentrations (C max s) of 60 to 80 g/ml and minimum plasma concentrations (C min s) of 5 to 20 g/m...

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

Cited by 45 publications

References 20 publications

Diet-Microbiota Interactions and their Implications for Healthy Living

Diet-Microbiota Interactions and their Implications for Healthy Living

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

Clinical Pharmacokinetics of Oral Controlled-Release 5-Fluorocytosine

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