{"doi":"10.1111/bph.16020","title":"Opioid‐induced microbial dysbiosis disrupts irinotecan (CPT‐11) metabolism and increases gastrointestinal toxicity in a murine model","abstract":"BACKGROUND AND PURPOSE: Opioids are commonly used for the management of cancer-associated pain and chemotherapy-induced diarrhoea. The chemotherapeutic irinotecan (CPT-11) causes severe gastrointestinal (GI) toxicity due to deconjugation of inactive metabolite SN-38 glucuronide (SN-38G) by bacterial β-glucuronidases to the active 7-ethyl-10-hydroxycamptothecin (SN-38). Opioids are known to cause gut microbial dysbiosis, this study evaluated whether CPT-11 anti-tumour efficacy and GI toxicity are exacerbated by opioid co-administration. EXPERIMENTAL APPROACH: Eight-week-old C57BL/6 male mice were co-administration with CPT-11 ± opioid. 16S rRNA sequencing was used for gut microbiome analysis. LC-MS analyses of plasma and intestinal extracts were performed to investigate the pharmacokinetic profile of CPT-11. Histological analysis and quantitative real-time polymerase chain reaction were used to determine the severity of intestinal tissue damage. Human liver microsome In vitro assay was performed to confirm the effects of opioids on CPT-11 metabolism. KEY RESULTS: Gut microbiome analysis showed that morphine treatment induced enrichment of β-glucuronidase-producing bacteria in the intestines of CPT-11-treated mice, resulting in SN-38 accumulation and exacerbation of GI toxicity in the small intestine. Oral administration of both antibiotics and glucuronidase inhibitor protected mice against GI toxicity induced with CPT-11 and morphine co-administration, implicating a microbiome-dependent mechanism. Additionally, morphine and loperamide decreased the plasma concentration of SN-38 and compromised CPT-11 anti-tumour efficacy, this seemed to be microbiome independent. CONCLUSION AND IMPLICATIONS: Gut microbiota play a significant role in opioid and chemotherapeutic agent drug-drug interactions. Inhibition of gut microbial glucuronidase may also prevent adverse GI effects of CPT-11 in patients on opioids.","journal":"British Journal of Pharmacology","year":2022,"id":253969,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9625,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":683848,"name":"Yaa Abu","orcid":"0000-0001-7285-0117","position":1,"is_corresponding":false},{"id":406992,"name":"Yue Zhang","orcid":"0000-0003-2128-8472","position":2,"is_corresponding":false},{"id":900471,"name":"Yuyin Zhou","orcid":"0000-0003-3751-7663","position":3,"is_corresponding":false},{"id":900472,"name":"Yun Xie","orcid":"0000-0002-4341-7426","position":4,"is_corresponding":false},{"id":900473,"name":"Yan Yan","orcid":"0000-0002-5385-9965","position":5,"is_corresponding":false},{"id":709302,"name":"Junyi Tao","orcid":"0000-0003-2638-5386","position":6,"is_corresponding":false},{"id":313792,"name":"Sundaram Ramakrishnan","orcid":"0000-0002-3102-9231","position":7,"is_corresponding":false},{"id":337783,"name":"Chi Chen","orcid":"0000-0001-9703-604X","position":8,"is_corresponding":false},{"id":313793,"name":"Sabita Roy","orcid":"0000-0002-6192-8289","position":9,"is_corresponding":false},{"id":313786,"name":"Jingjing Meng","orcid":"0000-0001-7104-608X","position":0,"is_corresponding":true}],"reference_count":47,"raw_metadata":null,"created_at":"2026-07-19T00:25:03.918844Z","pmid":"36562107","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}