Effect of Yueju Pill on the Pharmacokinetics and Antidepressant Effect of Fluoxetine in Rats.

INTRODUCTION: This study aims to investigate the effect of Yueju Pill (YJW) on the pharmacokinetics and antidepressant effect of Fluoxetine (FLX) in rats. METHODS: The depression rat model was established using lipopolysaccharide. Pharmacokinetics parameters of Fluoxetine were analyzed via HPLC. Behavioral changes were assessed using the open field test, sucrose preference test, and forced swim test. Gastrointestinal motility function was evaluated. The levels of IL-1β, IL-6, TNF-α, SOD, and MDA in Serum, and 5-HT, DA, NE, and BDNF in the hippocampus were measured by ELISA. Hippocampal histopathology and 16S rRNA gut microbiota sequencing were performed. RESULTS: AUC0-t (24.52 ± 1.09 mg/Lh), AUC0-∞ (25.09 ± 1.11 mg/Lh), Cmax (1.10 ± 0.04 mg/L), and t1/2 (12.63 ± 0.30 h) of FLX in the YJW group significantly increased, while CL/F (0.07 L/(hkg)) decreased. Pharmacodynamic studies demonstrated that the combination therapies, compared with monotherapies, significantly ameliorated depressive-like behaviors, restored neurotransmitter and BDNF levels, reduced pro-inflammatory cytokines, alleviated oxidative stress damage, and mitigated gastrointestinal motility disorders induced by FLX. Notably, the combination of YJW with low-dose FLX was particularly effective in alleviating gastrointestinal hypomotility. Histopathology revealed superior neuroprotective effects on hippocampal neurons in the combination groups. Gut microbiota analysis indicated that combination treatments, especially in the low-dose FLX group, more effectively reversed dysbiosis. DISCUSSION: YJW may alter the pharmacokinetics of FLX by modulating the activity of CYP enzymes and transporters. Further in vitro and in vivo research should be done to assess the effect of YJW on the activity of CYP enzymes and transporters. The combination therapy exerts synergistic antidepressant effects via multi-target and multi-pathway mechanisms, effectively regulating neurotransmitters, suppressing neuroinflammation, alleviating oxidative stress, and restoring gut microbiota homeostasis. The key molecular targets and core regulatory pathways need further investigation. CONCLUSION: YJW enhances the blood exposure of FLX by influencing pharmacokinetics and synergizes with FLX through multi-target mechanisms. The strategy of combining YJW with low-dose FLX not only enhances efficacy but also mitigates FLX-associated gastrointestinal adverse effects. It provides a basis for the combination of YJW and FLX, which highlights the gut-brain axis as a critical target for developing novel therapeutic strategies.