Cited by 121Pharmacogenetics and Drug MetabolismGut microbiota and healthDrug Transport and Resistance Mechanisms

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Intestinal anaerobic bacteria hydrolyse sorivudine, producing the high blood concentration of 5-(E)-(2-bromovinyl)uracil that increases the level and toxicity of 5-fluorouracil

Nakayama, Haruyuki, Kinouchi, Takemi, Kataoka, Keiko, Akimoto, Shigeru, Matsuda, Yoshiko, Ohnishi, Yoshinari·1997·Pharmacogenetics

DOI 10.1097/00008571-199702000-00005

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Abstract

Sorivudine, 1-beta-D-arabinofuranosyl-5-(E)-(2-bromovinyl)uracil, is a potent antiviral agent against varicella-zoster virus and herpes simplex virus type 1. However, sorivudine should not be used in combination with anticancer drugs such as 5-fluorouracil (5-FU) because (E)-5-(2-bromovinyl)uracil (BVU), a metabolite of sorivudine, inhibits the degradation of 5-FU, resulting in its accumulation in the blood and marked enhancement of the toxicity of 5-FU. Since phosphorolytic enzymes generate BVU from sorivudine, we investigated the distribution of the enzyme activity in rats. High activity was found in the cecal and large intestinal contents, while very low or no detectable activity in the liver, kidney, stomach, cecum, large intestine, and the stomach and small intestinal contents. These results suggest that intestinal microflora play an important role in BVU production. Therefore, we measured the phosphorylase activity in cell-free extracts from 23 aerobes, 16 anaerobes and a fungus. Bacteroides species B. vulgatus, B. thetaiotaomicron, B. fragilis, B. uniformis and B. eggerthii, dominant members of intestinal microflora, had high activity to convert sorivudine to BVU. To elucidate the contribution of intestinal microflora to BVU production in vivo, we administered sorivudine to rats treated with several antibiotics and measured the BVU concentration in the serum of rats. When sorivudine was given to rats treated with ampicillin or a mixture of bacitracin, neomycin and streptomycin, which decreased the numbers of viable aerobes and anaerobes, only a small amount of BVU was found in the serum. BVU concentration in the serum of rats treated with metronidazole to decrease the number of intestinal anaerobes was also very low. In contrast, BVU concentration in the serum of rats treated with kanamycin, which was used to decrease the number of aerobes selectively, was higher than that of non-treated rats. These results also suggest that BVU is produced by intestinal anaerobic bacteria especially Bacteroides species in vivo.

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“Intestinal flora reacts with sorivudine to generate (E)-5-(2-bromovinyl)uracil”
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“The negative side of the medal is represented by the cases of lethality due to increased toxicity of chemotherapy drugs caused by their xenometabolism; for instance, several years ago, Japanese authors reported the accumulation in blood of 5-fluorouracil (5-FU) sorivudine bi-therapy metabolites caused by Bacteroides s…”
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“Hence, co-administration of sorivudine and 5-FU induced the accumulation of 5-FU in the systemic circulation and consequently led to 5-FU-associated death (Nakayama et al. 1997; Diasio 1998).”
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“It is found that the gut microbial metabolite of sorivudine, bromovinyluracil inactivates DPD and thus limits detoxification of 5‐FU.(148) The drug–drug inter-”
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“thetaiotaomicron were found increasing the drug toxicity effect for sorivudine, a drug used for treating viral infections (Nakayama et al., 1997).”
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“A typical example is that co-administration of the antiviral drug solivudine with the antitumor drug 5-fluorouracil (5-FU) can increase circulating 5FU levels, resulting in 5-FU-related death, as the gut microbiota can transform solivudine into (E)-5-(2-bromovinyl)uracil (BVU) which is an inhibitor of hepatic dihydrop…”
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“Bacteroides also produce (E)-5-(2-bromovinyl) uracil metabolite, which increases the toxicity of sorivudine [16].”
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“For example, the active gut microbiota capable of producing bromovinyluracil can increase the systematic concentrations of 5-FU and caused the death of 16 patients in Japan [8,9].”
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“The mechanism of this severe toxicity was attributed to the generation of 5-(trans-2-bromovinyl)uracil (BVU) from sorivudine by gut flora (Nakayama et al., 1997).”
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“eggerthii) can hydrolyze sorivudine to (E)‐5‐(2‐bromovinyl) uracil, which inactivates the detoxification enzyme (57).”
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“The major side effect of this drug is that the BV-araU can be cleaved by intestinal mucosa flora to produce bromovinyl uracil (BVU; Nakayama et al., 1997).”
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Evaluation of capacity-limited first-pass effect through liver by three-points sampling in portal and hepatic veins and systemic artery.
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“(5) and (6) by comparing moment parameters, AUC and MRT, of the time course of 5-FU in the systemic blood after intraarterial and oral administration.”
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“Hence, it was shown that inhibition of DPD by gut Microflora generated BVU led to the deaths when SRV was co-administered with the 5-FU.(13)”
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“Evidently, the active gut microbiota, equipped with the capacity to synthesize bromovinyluracil, can exert profound regulatory inﬂuences on systemic 5-FU concentrations [17,18].”
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“The release of BVU from BVDU is reversible and occurs principally in the liver; that of BVU from BVaraU occurs primarily in the gut and is irreversible.”
BackgroundInfluential
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Authors: Nakayama, H., Kinouchi, T., Kataoka, K., Akimoto, S., Matsuda, Y., & Ohnishi, Y.
Affiliations: Tokushima University (JP)
ORCID: Kataoka, Keiko
Venue: Pharmacogenetics
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 1997-02
Volume: 7
Issue: 1
Pages: 35-43
ISSN: 0960-314X (ISSN-L)
DOI: 10.1097/00008571-199702000-00005
OpenAlex: W2016990995
Cited by: 120
References: 0
Citations by year: 2026: 1 · 2025: 3 · 2024: 7 · 2023: 8 · 2022: 8 · 2021: 13 · 2020: 15 · 2019: 13 · 2018: 6 · 2017: 6 · 2016: 4 · 2015: 7 · 2014: 3 · 2013: 4 · 2012: 3
FWCI: 1.68
Type: journal article
Language: en
Open access: closed
Locations: Pharmacogenetics (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords: sorivudine, 5-fluorouracil, gut microbiota, Bacteroides, drug-drug interactions, drug toxicity, antiviral agents, antibiotic-induced dysbiosis, Bacteroides fragilis
MeSH terms: Animals, Antiviral Agents, Arabinofuranosyluracil, Bacteria, Anaerobic, Bacteroides, Biotransformation, Bromouracil, Cecum, Fluorouracil, Gastric Mucosa, Gastrointestinal Contents, Intestinal Mucosa, Kidney, Liver, Male, Organ Specificity, Pentosyltransferases, Rats, Sprague-Dawley, Rats, Pyrimidine Phosphorylases

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Intestinal anaerobic bacteria hydrolyse sorivudine, producing the high blood concentration of 5-(E)-(2-bromovinyl)uracil that increases the level and toxicity of 5-fluorouracil

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