伊马替尼是治疗胃肠间质瘤的首选药物，多数患者在服药2年内出现耐药和疾病进展，与血浆药物谷浓度偏低相关。前期试验发现：胃切除术后患者连续给药，谷浓度出现显著下降，原因未知。基于文献和前期试验，我们提出假说：胃切除引起患者肠道pH增高，肠道菌群改变，使依赖肠道菌群的7α-脱氢酶活性增加，促进了胆汁酸生成石胆酸，石胆酸激活核受体PXR上调肝代谢酶和转运体的表达，增加药物代谢和排泄，最终造成谷浓度降低。本项目通过将患者和大鼠体内药物谷浓度与肠道菌群、7α-脱氢酶、石胆酸、PXR、代谢酶和转运体等进行相关性分析，阐明胃切除对患者和大鼠药物体内过程的影响及机制；再从细胞水平验证石胆酸激活PXR上调肝代谢酶和转运体的机制。本项目基于转化医学的理念，揭示胃切除状态下机体通过核受体调控肝代谢酶和转运体对伊马替尼体内过程的影响及机制，为伊马替尼临床个体化用药提供理论依据，为胃切除人群药物体内过程研究提供参考。

Imatinib is the first choice for treatment of gastrointestinal stromal tumor (GIST). The phenomenon that most of the GIST patients appeared drug resistant within 2 years may be related to the imatinib plasma trough concentrations in GIST patients. In our previous studies, the imatinib plasma trough concentrations of GIST patients after gastrectomy were declined significantly after consecutive drug administration. However, the reasons were still unclear. Based on the literature and early stage of experiments, we proposed that: the increasing intestinal pH and intestinal flora in GIST patients after gastrectomy have resulted in the increasing of intestinal flora dependent 7α-dehydroxylase, which could promote the bile acid generated to the lithocholic acid (LCA). Then, as an activator of PXR, LCA could activate the PXR to achieve raised metabolic enzymes and transporter expression. Finally, the metabolism and excretion of drug were increased, and the trough concentration of drug was declined. In this project, the intestinal flora, 7α-dehydroxylase,LCA, the activity of metabolic enzymes and the trough concentrations of GIST patients and rats after gastrectomy with different dosing cycles were correlation analysed to clarify the effects of gastrectomy on the pharmacokinetics of imatinib in GIST patients and rats after gastrectomy; Then, the mechanism of gastrectomy effecting the imatinib trough concentrations was validated by a variety of experiments using and cell model. The project was based on the concept of translational medicine to reveal the mechanism that, the raised metabolic enzymes and transporter by nuclear receptor could affect the pharmacokinetics of imatinib in vivo after gastrectomy. The results of this project could provide the basis for imatinib clinical personalized medicine and the reference for the study of pharmacokinetic process of drugs for gastrectomy group.