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ObjectiveN-butylphthalide (NBP) is a monomeric compound extracted from natural plant celery seeds, whether intestinal microbiota alteration can modify its pharmacokinetics is still unclear. The purpose of this study is to investigate the effect of intestinal microbiota alteration on the pharmacokinetics of NBP and its related mechanisms.MethodsAfter treatment with antibiotics and probiotics, plasma NBP concentrations in SD rats were determined by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The effect of intestinal microbiota changes on NBP pharmacokinetics was compared. Intestinal microbiota changes after NBP treatment were analyzed by 16S rRNA sequencing. Expressions of CYP3A1 mRNA and protein in the liver and small intestine tissues under different intestinal flora conditions were determined by qRT-PCR and Western Blot. KEGG analysis was used to analyze the effect of intestinal microbiota changes on metabolic pathways.ResultsCompared to the control group, the values of Cmax, AUC0-8, AUC0-∞, t1/2 in the antibiotic group increased by 56.1% (P0.001), 56.4% (P0.001), 53.2% (PPmax values decreased by 57.1% (P0.001) and 28.6% (PConclusionAntibiotic treatment could affect the intestinal microbiota, decrease CYP3A1 mRNA and protein expressions and increase NBP exposure in vivo by inhibiting pathways related to NBP metabolism.