YB-1调控肠道P-gp对达比加群酯在高龄人群中的药代动力学影响及机制研究

高龄人群肠道P-糖蛋白（P-gp）功能下降会导致其底物药代动力学变化，直接关系到安全性和有效性。目前尚缺乏P-gp底物在高龄人群中药动学特征的预测方法以支持剂量调整，阐明该过程的调控机制是实现精准预测的关键。申请人在前期研究中发现，P-gp的转录调节因子Y-box结合蛋白1（YB-1）在老龄大鼠的肠道组织表达降低，细胞模型中沉默该基因后，P-gp诱导性表达显著下降，提示YB-1可能是高龄下调肠道P-gp表达的关键因子。因此，本项目拟基于肠道P-gp探针药物达比加群酯（DABE），进一步验证YB-1表达对肠道P-gp的影响，建立YB-1调控的肠道P-gp表达与其外排DABE能力的相关性，以此更新申请人前期建立的中国老年人生理药动学基础模型，并进行临床数据验证。本研究结果将提高DABE在高龄患者中药动学特征的预测准确度，为DABE及其他P-gp底物在高龄患者的临床精准用药提供数据基础。

The decreased function of intestinal P-glycoprotein (P-gp) in population with advanced age leads to the pharmacokinetic changes of its substrates, which is directly related to safety and efficacy. At present, there is still no method to predict the pharmacokinetic characteristics of P-gp substrates in population with advanced age to support dose adjustment. To clarify the regulatory mechanism of this process is the key to achieve accurate prediction. In the previous study, the applicant found that the expression of P-gp transcription regulator Y-box binding protein 1 (YB-1) was reduced in the intestine of aged rats, and the induced expression of P-gp was significantly decreased after the gene was silenced in cell model, suggesting that YB-1 may be the key factor to down-regulate the expression of P-gp in the intestine. Therefore, this project is based on intestine P-gp probe drug, dabigatran etexilate (DABE), to further verify the effect of YB-1 expression on intestinal P-gp and establish the correlation between YB-1-regulated intestinal P-gp expression and its ability of DABE efflux. Finally, the physiological based pharmacokinetic model of Chinese elderly people established earlier by the applicant was updated and verified by the clinical data. The results of this study will improve the prediction accuracy of pharmacokinetic characteristics of DABE in patients with advanced age and provide data basis for precise medication of DABE and other P-gp substrates in the elderly patients.