抄録
Hypothesis: Simotinib Hydrochloride (SIM6802), which is a new epidermal growth factor receptor-tyrosine kinases inhibitor (EGFR-TKI), is often prescribed for cancer patients with comorbidities and has serious adverse effects gastrointestinal physiology. The drug-drug interactions (DDI) between simotinib and other drugs in combination and the underlying mechanism of its gastrointestinal toxicity remains unclear. We hypothesized that the DDI and the gastrointestinal toxicity of simotinib was related to its effects on the permeability of intestine. Methods: To determine the intestinal absorption ability, pharmacokinetic studies and in situ loop assay were used. The intestinal permeability was measured by Caco-2 transwell model. Real time PCR and western blots were applied to detecting the expression changes of cell junction genes. Results: Our research demonstrated that simotinib upregulated the absorption of cefaclor, valaciclovir and acyclovir. The increase of non-selective absorption was caused by the low expression of cell junction gene afadin-6 and the increasing of paracellular permeability in intestinal epithelial cells after simotinib treatment. Conclusion: These findings revealed that simotinib upregulated intestinal absorption by increasing the paracellular permeability of intestinal epithelial cells. Our research provides theoretical bases for better formulation of EGFR-TKIs to alleviate adverse gastrointestinal effects and also provides guidance for clinical administration of simotinib.
