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.