肠道菌群介导的他克莫司药动学个体差异及其调控机制研究

Tacrolimus is the cornerstone of most immunosuppresive regimens in organ transplantation, but its use is complicated by high variability and narrow therapeutic window. High inter-individual and intra-individual variability could not be explained by gene polymorphisms. Pilot studies demonstrated the association between gut mircobiota and tacrolimus blood concentration. Our preliminary experimental results show that the tacrolimus exposure difference in vivo may be related to gut microbiota differences. Gut microbiota can regulate host metabolism, drug-metabolism enzymes and transporters with high individual variability and dynamic change. It is a potential biomarker for personalized medicine. Both the metabolic enzyme CYP3A and the transporter p-gp are involved in the pharmacokinetic process of tacrolimus. We speculate that gut microbiota may affect the pharmacokinetic process of tacrolimus by regulating CYP3A and p-gp. Based on the above mentioned, first, at the animal level, candidate gut microbiota affecting the pharmacokinetic behavior of tacrolimus will be screened out and further verified in human body. Second, to explore the regulatory basis of the target bacteria's on tacrolimus pharmacokinetics, and to elaborate its regulatory effect on intestinal/liver CYP3A and p-gp. Quantitative pharmacological modeling was used to evaluate the clinical value of gut microbiota in renal transplant recipients. Through the studies, the influence mechanism of gut microbiota on individual variability of tacrolimus pharmacokinetics was elaborated. These efforts would provide a new strategy for personalized medicine of tacrolimus.

他克莫司(Tac)疗效显著，但治疗窗窄、个体差异大。遗传药理学不能完全解释Tac个体差异。已有小样本研究表明Tac剂量需求与肠道菌群差异有关，课题组预实验有类似提示：Tac体内暴露量差异可能与肠道菌群结构变异相关。肠道菌群对宿主代谢酶和转运体等具有调控作用，个体差异大且动态变化，是潜在的个体化用药生物标记物。我们推测肠道菌群可能通过调控CYP3A和P-gp而影响Tac药动学过程。基于上述推测：拟在预实验基础上，筛选出Tac药动学行为相关的候选肠道菌；并在人体上进一步验证，得到目标肠道菌；在动物水平上探讨目标菌对Tac药动学影响的调控基础，阐述其影响Tac体内暴露的药动学环节及对肠道及肝脏CYP3A和P-gp的调控作用；在肾移植受者群体中，采用定量药理学模型化策略评价肠道菌群的临床应用价值。通过以上研究，阐述肠道菌群对Tac药动学个体差异的影响机制，为Tac临床个体化给药提供新思路。

他克莫司(Tac)疗效显著，但治疗窗窄、个体差异大。现已知因素不能完全解释Tac个体差异。已有小样本研究表明Tac剂量需求与肠道菌群差异有关，课题组预实验表明：经不同抗菌药物（VAN，IPM、ABX混合组）处置后，Tac暴露量呈不同程度升高，推测Tac体内暴露量受肠道菌调节。肠道菌群对宿主代谢酶和转运体等具有调控作用，个体差异大且动态变化，是潜在的个体化用药生物标记物。我们推测肠道菌群可能通过调控CYP3A和P-gp而影响Tac药动学过程。基于上述推测：课题组在预实验基础上，进一步筛选出Tac药动学行为相关的候选肠道菌；在动物水平上探讨目标菌对Ta c药动学影响的调控基础，阐述其影响Tac体内暴露的药动学环节及对肠道及肝脏CYP3A和P-gp 的调控作用；在肾移植受者群体中，采用定量药理学模型化策略评价肠道菌群的临床应用价值。结果表明：1. 经不同抗菌药物处置后，大鼠肠道菌变化明显，厚壁菌门总体降低的情况下，下属四大菌目：梭菌目、Selenomonadales、乳酸杆菌目、丹毒丝菌目变化方向不一致；大鼠粪便中各短链脂肪酸（SCFA）呈不同程度降低（丁酸下降更明显），补充SCFA后，tac暴露量升高程度降低； 2. SCFA影响肠道不同肠段P-gp mRNA表达量，对肝脏的影响无差异；SCFA对肝脏cyp3a mRNA影响不明显，而对肠道各肠段的影响未知（肠段cyp3a mRNA表达量低，未检测出）；提示：肠道菌可能通过调控肠道P-gp mRNA表达量影响Tac体内暴露量；3.基于多种混杂因素建立Tac临床个体化给药模型。通过以上研究，阐述肠道菌群对Tac药动学个体差异的影响机制，为Tac临床个体化给药提供新思路。