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.

Changes in Plasma Metabolic Signature upon Acute and Chronic Morphine Administration in Morphine-Tolerant Mice

“…In particular, metabolic changes in morphine-tolerant mice were mitigated, raising the question of whether changes in the plasma metabolites following acute morphine intake were contributing to morphine analgesic effects and whether they could serve as tolerance indicators. The role of metabolic changes in morphine-mediated pathologies [ 43 , 51 , 52 , 53 , 54 , 55 ] demands additional studies. Our findings warrant further investigation in other morphine tolerance models and humans.…”

The interplay between the microbiota and opioid in the treatment of neuropathic pain

“…Recent research has revealed that morphine treatment induces an enrichment of bacteria producing β-glucuronidase in the mouse gut. This leads to the accumulation of chemotherapy drugs in the intestine, culminating in the onset of gut dysbiosis ( Meng et al, 2023 ). For cancer patients undergoing long-term opioid treatment for pain management, the development of interventional drugs targeting the gut microbiota associated with this treatment could potentially mitigate the adverse effects of chemotherapy.…”

Pharmacokinetic study of the interaction between luteolin and magnoflorine in rats

“…Adverse drug interaction between different drugs or between different active ingredients would result in therapy failure and even toxicity, which was considered a risk factor that threatens patients' health and even caused deaths (Chee et al, 2011). For example, the application of opioids induced microbial dysbiosis, further affected the metabolism of irinotecan, and increased the risk of gastrointestinal toxicity (Meng et al, 2023). Cyperus rotundus L. aqueous, Areca catechu L., and St. John's wort extracts suppressed the pharmacological effect of digoxin during co‐administration via inducing P‐gp (Zhuang et al, 2023).…”