Irinotecan induces intestinal atrophy and compromises duodenal motility and mucosal permeability: in vivo and in vitro evaluations

PURPOSE: Intestinal toxicity is a major adverse effect of irinotecan (IRT) chemotherapy, and effective preventive treatments are lacking. This study evaluated the impact of IRT on (i) duodenal motility and mucosal barrier function, (ii) histopathological changes along the small intestine and colon, and (iii) faecal water content, to improve understanding of IRT-induced intestinal injury and support development of future therapeutic strategies. METHODS: Anaesthetized Sprague-Dawley rats underwent in situ duodenal perfusion to quantify the effects of intravenous (i.v.) IRT on duodenal motility and blood-to-lumen clearance of ³H-mannitol (paracellular route). In separate experiments, intestinal toxicity was induced by intraperitoneal (i.p.) IRT. After 72 h, rats were sacrificed and the small intestine and colon collected for histopathological evaluation. Body weight and faecal water content were assessed. Additionally, the effects of IRT and its active metabolite SN-38 on cell viability were examined in HCT116 cells. RESULTS: IRT (60 mg/kg, i.v.) markedly increased duodenal motility (+ 277%) and mucosal paracellular permeability (+ 85%) immediately after administration. At 72 h after administration, IRT (180-200 mg/kg, i.p.) reduced villus length in the duodenum (- 52%, - 45%) and jejunum (- 37%, - 33%), with no significant effect in the ileum, and increased jejunal crypt depth (+ 48%, + 41%). In addition, IRT (i.p.) elevated faecal water content (+ 19%, + 16%) and reduced body weight (- 10%, - 13%). In vitro, IRT and SN-38 decreased HCT116 viability in a concentration-dependent manner, with IC₅₀ values of 19.4 µM and 12.8 nM. CONCLUSION: IRT increases duodenal motility, disrupts mucosal barrier integrity, induces diarrhoea, and causes small-intestinal injury. SN-38 shows substantially higher cytotoxic potency. These findings provide mechanistic insight into IRT-induced intestinal toxicity and may inform development of strategies to mitigate gastrointestinal side effects in cancer patients.