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Pathophysiology of neratinib-induced diarrhea in male and female rats: microbial alterations a potential determinant
Kate R Secombe1, Imogen A Ball2, Joseph Shirren2
1Adelaide Medical School, University of Adelaide, Level 2 Helen Mayo Building South, Frome Rd, Adelaide, South Australia, 5005, Australia. kate.secombe@adelaide.edu.au.
Background:
Neratinib is a potent irreversible pan-ErbB tyrosine kinase inhibitor, approved by the FDA for extended adjuvant treatment of HER2-positive breast cancer. Diarrhea is the most frequently observed adverse event with tyrosine kinase inhibitor therapy. In this study, we developed a reproducible model for neratinib-induced diarrhea in male and female rats.
Methods:
At first, male rats were treated with neratinib at 15, 30 or 50 mg/kg or vehicle control via oral gavage for 28 days (total n = 12). Secondly, we compared outcomes of male (n = 7) and female (n = 8) rats, treated with 50 mg/kg neratinib.
Results:
Rats treated with a 50 mg/kg daily dose of neratinib had a reproducible and clinically relevant level of diarrhea and therefore was confirmed as an appropriate dose. Male rats treated with neratinib had significant changes to their gut microbiome. This included neratinib-induced increases in Ruminococcaceae (P = 0.0023) and Oscillospira (P = 0.026), and decreases in Blautia (P = 0.0002). On average, female rats experienced more significant neratinib-induced diarrhea (mean grade 1.526) compared with male rats (mean grade 1.182) (P < 0.0001). Neratinib caused a reduction in percentage weight gain after 28 days of treatment in females (P = 0.0018) compared with vehicle controls. Females and males both showed instances of villus atrophy and fusion, most severely in the distal ileum. Serum neratinib concentration was higher in female rats compared to male rats (P = 0.043).
Conclusions:
A reproducible diarrhea model was developed in both female and male rats, which indicated that diarrhea pathogenesis is multifactorial, including anatomical disruption particularly evident in the distal ileum, and alterations in microbial composition.
Insights
Neratinib treatment in rats caused reproducible diarrhea, impacting gut microbiome and intestinal structure. Female rats experienced more severe diarrhea and higher drug concentrations than males.
Area of Science:
- Pharmacology
- Gastroenterology
- Oncology
Background:
- Neratinib is an FDA-approved irreversible pan-ErbB tyrosine kinase inhibitor for HER2-positive breast cancer.
- Diarrhea is a common adverse event associated with tyrosine kinase inhibitor therapy.
- A reproducible animal model is crucial for studying neratinib-induced diarrhea.
Purpose of the Study:
- To develop a reproducible rat model for neratinib-induced diarrhea.
- To investigate the effects of neratinib on gut microbiome and intestinal morphology.
- To compare neratinib-induced diarrhea severity in male and female rats.
Main Methods:
- Male rats were treated with neratinib (15, 30, or 50 mg/kg) or vehicle for 28 days.
- Male and female rats were treated with 50 mg/kg neratinib to compare outcomes.
- Gut microbiome composition, weight gain, intestinal histology, and serum drug concentrations were analyzed.
Main Results:
- A 50 mg/kg daily dose of neratinib induced reproducible diarrhea in rats.
- Neratinib altered gut microbiome composition in male rats, increasing Ruminococcaceae and Oscillospira while decreasing Blautia.
- Female rats exhibited more severe diarrhea, reduced weight gain, and higher serum neratinib concentrations compared to males. Both sexes showed distal ileum villus atrophy and fusion.
Conclusions:
- A reproducible neratinib-induced diarrhea model was established in male and female rats.
- Diarrhea pathogenesis is multifactorial, involving anatomical disruption (distal ileum) and microbial alterations.
- Sex differences in neratinib pharmacokinetics and diarrhea severity were observed.
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