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
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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The hydrolysis of sorivudine to bromovinyluracil, followed by host metabolism to an inhibitor of dihydropyrimidine dehydrogenase, may lead to toxicity due to inhibited degradation and increased concentrations of coadministered 5-fluorouracil.
“The hydrolysis of the antiviral drug sorivudine to bromovinyluracil, which is then subsequently metabolized by the host to an inhibitor of host dihydropyrimidine dehydrogenase, may lead to toxicity due to inhibited degradation and increased concentrations of coadministered 5-fluorouracil (5-FU) (Nakayama et al., 1997).”
From Gut reactions: Breaking down xenobiotic–microbiome interactions (2019) · cites this paper as Nakayama et al., 1997
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“bromovinyl) uracil (BVU) metabolite Nakayama et al.(44)”
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“,Klebsiella pneumoniae,(77) and/or the anaerobic Bacteroides species.(78) Even at the 40 mg once-daily oral dosage regimen for 10 consecutive days,(57) BVaraU leads to a profound depression of DPD activity, and recovery of DPD activity occurred only within 4 weeks of completion of BVaraU therapy.”
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“, a normal inhabitant of the gut microbiome, can accelerate the conversion of sorivudine (synthetic analogue of thymidine) into bromovinyluracil (BVU), which accumulates in the blood, resulting in increased toxicity in patients taking oral UFT (a combination of ftorafur, a 5FU prodrug, with uracil) [143].”
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“…phosphorylase, encoded by the pdp gene and present in Escherichia coli and many Bacteroides species, and has been found involved in the metabolism of sorivudine 99 and brivudine 10 (Figure 3(B)), with both drugs leading to the formation of the toxic compound bromovinyluracil.”
BackgroundOrally Administered Drugs and Their Complicated Relationship with Our Gastrointestinal Tract
Bashiardes, S., & Christodoulou, C. (2024) · Microorganisms · doi:10.3390/microorganisms12020242 · Cited by 30 · see citing works
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“Antibiotic pretreatment in rats significantly increased the C max of sorivudine by 2 fold and decreased serum BVU level to nearly zero— also significantly reducing PyNPase activity in the cecum, while activity in the liver remained unaffected [17].”
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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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Xu, Y., Du, H., Chen, Y., Ma, C., Zhang, Q., Li, H., Xie, Z., & Hong, Y. (2023) · Critical Reviews in Microbiology · doi:10.1080/1040841x.2023.2233605 · Cited by 26 · see citing works
“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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Luo, Y., & Zhou, T. (2021) · Medicinal Research Reviews · doi:10.1002/med.21805 · Cited by 20 · see citing works
“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-”
BackgroundWang, Z., Hopson, L. M., Singleton, S. S., Yang, X., Jogunoori, W. S., Mazumder, R., Obias, V., Lin, P., Nguyen, B.-N. H., Yao, M. D., et al. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2021.166179 · Cited by 20 · see citing works
The rising dominance of microbiology: what to expect in the next 15 years?
Kumar, R., Sood, U., Kaur, J., Anand, S., Gupta, V., Patil, K. S., & Lal, R. (2021) · Microbial Biotechnology · doi:10.1111/1751-7915.13953 · Cited by 18 · see citing works
“thetaiotaomicron were found increasing the drug toxicity effect for sorivudine, a drug used for treating viral infections (Nakayama et al., 1997).”
BackgroundSystematic mapping of drug metabolism by the human gut microbiomePreprint
Chankhamjon, P., Javdan, B., Lopez, J. G., Hull, R., Chatterjee, S., & Donia, M. S. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/538215 · Cited by 18 · see citing works
A mechanism-based understanding of altered drug pharmacokinetics by gut microbiota
Gulnaz, A., Chang, J., Maeng, H., Shin, K., Lee, K., & Chae, Y. (2022) · Journal of Pharmaceutical Investigation · doi:10.1007/s40005-022-00600-z · Cited by 17 · see citing works
Microbial metabolites as modulators of host physiology
Joyce, S. A., & Clarke, D. J. (2024) · Advances in microbial physiology/Advances in Microbial Physiology · doi:10.1016/bs.ampbs.2023.12.001 · Cited by 18 · see citing works
Curious Discoveries in Antiviral Drug Development: The Role of Serendipity
Clercq, E. D. (2015) · Medicinal Research Reviews · doi:10.1002/med.21340 · Cited by 16 · see citing works
Giménez‐Bastida, J. A., Carreras, L. M., Moya-Pérez, Á., & Llopis, J. M. L. (2017) · Journal of Pharmaceutical Sciences · doi:10.1016/j.xphs.2017.10.031 · Cited by 17 · see citing works
MagMD: Database summarizing the metabolic action of gut microbiota to drugs
Zhou, J., Ouyang, J., Gao, Z., Qin, H., Wu, J., & Shi, T. (2022) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2022.11.021 · Cited by 13 · see citing works
“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…”
BackgroundComplex influences of gut microbiome metabolism on various drug responses
Chae, S., Kim, D. J., & Cho, J. (2020) · Translational and Clinical Pharmacology · doi:10.12793/tcp.2020.28.e3 · Cited by 12 · see citing works
“Bacteroides also produce (E)-5-(2-bromovinyl) uracil metabolite, which increases the toxicity of sorivudine [16].”
BackgroundLin, E., Huang, Y., Yang, P.-C., et al. (2023) · Biomolecules · doi:10.3390/biom13010149 · Cited by 12 · see citing works
“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].”
BackgroundHGMMX: Host Gut Microbiota Metabolism Xenobiotics Database
Kolodnitsky, A. S., Ионов, Н. С., Rudik, A. V., Filimonov, D. A., & Poroikov, V. (2023) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.3c00837 · Cited by 10 · see citing works
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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).”
BackgroundAntiviral Activity of Nucleoside Analogues: The BVDU Connection
Clercq, E. D. (2002) · Elsevier eBooks · doi:10.1016/b978-044450951-2/50015-1 · Cited by 11 · see citing works
Klemets, A., Reppo, I., Krigul, K. L., Volke, V., Aasmets, O., & Elin, O. (2026) · Scientific Reports · doi:10.1038/s41598-026-36318-3 · Cited by 12 · see citing works
Role of the microbiome in systemic therapy for pancreatic ductal adenocarcinoma (Review)
Huang, X., Mao, L., Hou, S., & Tian, B. (2021) · International Journal of Oncology · doi:10.3892/ijo.2021.5281 · Cited by 10 · see citing works
“eggerthii) can hydrolyze sorivudine to (E)‐5‐(2‐bromovinyl) uracil, which inactivates the detoxification enzyme (57).”
BackgroundThe Modulation of Drug Efficacy and Toxicity by the Gut Microbiome
Wilson, I. D., & Nicholson, J. K. (2014) · Molecular and integrative toxicology · doi:10.1007/978-1-4471-6539-2_15 · Cited by 9 · see citing works
Naik, A., & Misra, S. K. (2021) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.1c02736 · Cited by 8 · see citing works
The Gut Microbiome in Colorectal Cancer
Piawah, S., Walker, E. J., Blarigan, E. L. V., & Atreya, C. E. (2022) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2022.03.001 · Cited by 8 · see citing works
Drug Response Diversity: A Hidden Bacterium?
Hannachi, N., & Camoin‐Jau, L. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11050345 · Cited by 8 · see citing works
Li, L., Dutschman, G. E., Gullen, E. A., et al. (2000) · Molecular Pharmacology · doi:10.1124/mol.58.5.1109 · Cited by 7 · see citing works
“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).”
Gnatzy, L., Ismailos, G., Vertzoni, M., & Reppas, C. I. (2023) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2023.106510 · Cited by 6 · see citing works
Peiffer, D. S. (2020) · Food Frontiers · doi:10.1002/fft2.40 · Cited by 6 · see citing works
Microbiota in cancer chemoradiotherapy resistance
He, Y., Liu, Q. W., Liao, H. X., & Xu, W. W. (2020) · Clinical and Translational Medicine · doi:10.1002/ctm2.250 · Cited by 6 · see citing works
Ueda, S., Yamaoka, K., Yui, J., et al. (2002) · Pharmaceutical Research · doi:10.1023/a:1016165101921 · Cited by 6 · see citing works
“(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.”
BackgroundGut Microbiota and Its Role in Metabolism of Common Drugs–A Short Review
Jamwal, R., & Goswami, S. K. (2015) · Pharmacology Toxicology and Biomedical Reports · doi:10.5530/ptb.1.3.2 · Cited by 4 · see citing works
“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)”
BackgroundCrystal Structure of DNA Replication Protein SsbA Complexed with the Anticancer Drug 5-Fluorouracil
Su, H.-H., Huang, Y., Lien, Y., Yang, P.-C., & Huang, C.-Y. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241914899 · Cited by 4 · see citing works
“Evidently, the active gut microbiota, equipped with the capacity to synthesize bromovinyluracil, can exert profound regulatory influences on systemic 5-FU concentrations [17,18].”
Velez-Haro, J. M., Pérez-Rodríguez, F., Velazquéz‐Marquez, S., Medina, H. R., & Velázquez-Márquez, N. (2024) · Springer eBooks · doi:10.1007/978-3-031-62558-9_16 · Cited by 4 · see citing works
Antiviral Drug Development – Success and Failure: A Personal Perspective with a Japanese Connection
Clercq, E. D. (2012) · Antiviral chemistry & chemotherapy · doi:10.3851/imp2396 · Cited by 3 · see citing works
“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.”
BackgroundInfluentialGut microbiota and chemoradiotherapy response in rectal cancer: Biomarker opportunities
Taoum, C., Devaux, A., Rouanet, P., Colombo, P., Boucher, D., & Bonnet, M. (2025) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2025.104974 · Cited by 3 · see citing works
Gut resistome profiling reveals high diversity and fluctuations in pancreatic cancer cohorts
Liu, X., Li, K., Yang, Y. K., et al. (2024) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2024.1354234 · Cited by 2 · see citing works
- Authors
- Nakayama, H., Kinouchi, T., Kataoka, K., Akimoto, S., Matsuda, Y., & Ohnishi, Y.
- Affiliations
- Tokushima University (JP)
- ORCID
- Kataoka, Keiko
- Venue
- Pharmacogenetics
- Published
- 1997-02
- Volume
- 7
- Issue
- 1
- Pages
- 35-43
- ISSN
- 0960-314X (ISSN-L)
- 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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