Targeting Regorafenib-Induced Toxicity through Inhibition of Gut Microbial β-Glucuronidases

Ervin, Samantha M.; Hanley, Ronan P; Lim, Lauren; Walton, William G.; Pearce, Kenneth H.; Bhatt, Aadra P.; James, Lindsey I.; Redinbo, Matthew R.

doi:10.1021/acschembio.9b00663

Cited by 52 publications

(42 citation statements)

References 38 publications

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“…However, no systematic characterization of microbial enzymes that process particular classes of medications or a list of medications that are metabolized by such enzymes were presented. For example, the β-glucuronidase activity has been reported to cause severe toxicity for several medications (such as irinotecan [ 10 , 11 , 58 ], diclofenac [ 59 ], mycophenolate mofetil [ 60 ], and regorafenib [ 61 ]) and it has been demonstrated that this toxicity can be reduced by co-administration of β-glucuronidase inhibitors [ 59 , 61 ]. However, one may wonder if there are other drugs that could be affected by β-glucuronidase.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to all previously mentioned drugs, several others listed in S1 Data were reported to be affected by β-glucuronidase, including irinotecan [ 11 , 78 , 79 ], regorafenib [ 61 ], tamoxifen [ 80 ], mitiglinide [ 81 ], clozapine [ 82 ], and zidovudine [ 83 ]. In summary, among the 100 drugs that we predicted to be metabolized by β-glucuronidases, we compiled evidence supporting the prediction for over 20 of them.…”

Section: Discussionmentioning

confidence: 99%

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Predicting drug-metagenome interactions: Variation in the microbial β-glucuronidase level in the human gut metagenomes

2021

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Characterizing the gut microbiota in terms of their capacity to interfere with drug metabolism is necessary to achieve drug efficacy and safety. Although examples of drug-microbiome interactions are well-documented, little has been reported about a computational pipeline for systematically identifying and characterizing bacterial enzymes that process particular classes of drugs. The goal of our study is to develop a computational approach that compiles drugs whose metabolism may be influenced by a particular class of microbial enzymes and that quantifies the variability in the collective level of those enzymes among individuals. The present paper describes this approach, with microbial β-glucuronidases as an example, which break down drug-glucuronide conjugates and reactivate the drugs or their metabolites. We identified 100 medications that may be metabolized by β-glucuronidases from the gut microbiome. These medications included morphine, estrogen, ibuprofen, midazolam, and their structural analogues. The analysis of metagenomic data available through the Sequence Read Archive (SRA) showed that the level of β-glucuronidase in the gut metagenomes was higher in males than in females, which provides a potential explanation for the sex-based differences in efficacy and toxicity for several drugs, reported in previous studies. Our analysis also showed that infant gut metagenomes at birth and 12 months of age have higher levels of β-glucuronidase than the metagenomes of their mothers and the implication of this observed variability was discussed in the context of breastfeeding as well as infant hyperbilirubinemia. Overall, despite important limitations discussed in this paper, our analysis provided useful insights on the role of the human gut metagenome in the variability in drug response among individuals. Importantly, this approach exploits drug and metagenome data available in public databases as well as open-source cheminformatics and bioinformatics tools to predict drug-metagenome interactions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Predicting drug-metagenome interactions: Variation in the microbial β-glucuronidase level in the human gut metagenomes

2021

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“…In addition, the risks associated with REG therapy may be increased by other underlying factors, including prior oncologic and non-oncologic therapies, concomitant medications and other comorbidities. 43 – 46 …”

Section: Discussionmentioning

confidence: 99%

Dose reduction and discontinuation of standard-dose regorafenib associated with adverse drug events in cancer patients: a systematic review and meta-analysis

et al. 2020

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Background: Regorafenib (REG) is an oral multikinase inhibitor used in colorectal cancer, gastrointestinal stromal tumour and hepatocellular carcinoma. Several adverse events (AEs) are commonly reported during REG administration, and strategies for managing AEs in everyday clinical practice include supportive care, dose modifications and, when necessary, treatment withdrawal. We performed a systematic review and meta-analysis to assess the schedule treatment modifications of REG associated with AEs across randomized controlled clinical trials (RCTs). Methods: Eligible studies included RCTs assessing standard dose REG versus placebo. Outcomes of interest included: AE-related permanent discontinuation, dose interruptions and dose reductions. Results: We retrieved all the relevant RCTs through PubMed/Med, Cochrane library and EMBASE: 7 eligible studies involving a total of 2099 patients (Regorafenib: 1362; placebo: 737) were included in our analysis. The use of REG was associated with higher incidence and risk of all outcomes of interest when compared with placebo. The incidences of permanent discontinuation, dose interruptions and dose reductions in patients receiving REG were 9.7%, 57.2% and 47%, respectively, versus 3.3%, 16.7% and 7.7% of placebo group; compared with placebo, the summary relative risks (RRs) of permanent discontinuation, dose interruptions and dose reductions in REG arm were 2.80 (95% CI 1.85–4.22), 3.21 (95% CI 2.59–3.99) and 6.02 (95% CI 3.28–11.03), respectively. Conclusions: Treatment with REG at the standard dose of 160 mg is associated with a significant increase in AE-related permanent discontinuation, dose interruptions and dose reductions. Prompt identification and management of AEs seem mandatory to obtain maximal benefit from REG treatment. In the current landscape, dose personalization of REG may have the potential to improve quality of life, minimize treatment discontinuation and maximize patient outcomes.

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“…Regorafenib is a multikinase inhibitor with excellent antitumor effects. Microbial reactivation of regorafenib-glucuronide in the gastrointestinal tract by β -glucuronidases is the major cause of gastrointestinal toxicity 164 . Similar to that of CPT-11 and diclofenac, inhibition of microbial β -glucuronidases is believed to reduce regorafenib-induced toxicity 164 .…”

Section: Gut Microbiota-oriented Precision Medicinementioning

confidence: 99%

“…Microbial reactivation of regorafenib-glucuronide in the gastrointestinal tract by β -glucuronidases is the major cause of gastrointestinal toxicity 164 . Similar to that of CPT-11 and diclofenac, inhibition of microbial β -glucuronidases is believed to reduce regorafenib-induced toxicity 164 . These studies suggested the possibility of the combinational use of bacterial β -glucuronidases for reducing the toxicity of drugs; however, additional clinical studies should be carried out to prove the feasibility of this approach.…”

Section: Gut Microbiota-oriented Precision Medicinementioning

confidence: 99%

Targeting gut microbiota for precision medicine: Focusing on the efficacy and toxicity of drugs

Feng

Liu

et al. 2020

Theranostics

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Intra- and interindividual variation in drug responses is one major reason for the failure of drug therapy, drug toxicity, and even the death of patients. Precision medicine, or personalized medicine, is a field of medicine that customizes an individual's medical diagnosis and treatment based on his/her genes, microbiomes, environments, etc. Over the past decade, a large number of studies have demonstrated that gut microbiota can modify the efficacy and toxicity of drugs, and the extent of the modification varies greatly from person to person because of the variability of the gut microbiota. Personalized manipulation of gut microbiota is an important approach to rectify the abnormal drug response. In this review, we aim to improve drug efficacy and reduce drug toxicity by combining precision medicine and gut microbiota. After describing the interactions between gut microbiota and xenobiotics, we discuss (1) the effects of gut microbiota on drug efficacy and toxicity and the corresponding mechanisms, (2) the variability of gut microbiota, which leads to variation in drug responses, (3) the biomarkers used for the patient stratification and treatment decisions before the use of drugs, and (4) the methods used for the personalized manipulation of gut microbiota to improve drug outcomes. Overall, we hope to improve the drug response by incorporating the knowledge of gut microbiota into clinical practice.

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Targeting Regorafenib-Induced Toxicity through Inhibition of Gut Microbial β-Glucuronidases

Cited by 52 publications

References 38 publications

Predicting drug-metagenome interactions: Variation in the microbial β-glucuronidase level in the human gut metagenomes

Predicting drug-metagenome interactions: Variation in the microbial β-glucuronidase level in the human gut metagenomes

Dose reduction and discontinuation of standard-dose regorafenib associated with adverse drug events in cancer patients: a systematic review and meta-analysis

Targeting gut microbiota for precision medicine: Focusing on the efficacy and toxicity of drugs

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