霉酚酸对中国肝移植患者IMPDH与淋巴细胞活化影响的个体差异机制研究

Mycophenolic acid (MPA) exerts its immunosuppressive effect through inhibiting the activity of inosine 5′- monophosphate dehydrogenase (IMPDH) and further influence the proliferation of T cell. The variation of MPA effeciency and adverse effect is associated with inter-individual difference of MPA pharmacokinetics and pharmacodynamics. We found that various factors have influence on MPA pharmacokinetics and IMPDH acitity. However, the relationship between IMPDH activity and T cell proliferation and the mechanism of interindividual difference of MPA impaction on this process is still unclear. In this proposal we will futher study the variation of MPA pharmacokinetics in peripheral blood mononuclear cell (PBMC) and its correlation with MPA in plasma. Genetic polymorphism of IMPDH1 and IMPDH2 and the correlation with IMPDH activity will be determined. The proliferation of T cell and its surface antigen in animal model and liver transplant recipients will be determined by flow cytometric assay. The PK/PD relationship between IMPDH activity and T cell proliferation and the impaction of MPA will be established by NONMEM method. The influence of various factors on the pharmacodynamics of Chinese liver transplant patients will be studied by pharmacometric method and this will be useful in the rational usage of MPA.

霉酚酸(MPA)通过抑制次黄嘌呤核苷酸脱氢酶 (IMPDH)活性进而影响T细胞增殖发挥免疫抑制作用，MPA药动学与药效学个体差异对疗效与不良反应有较大影响。我们已发现MPA药动学过程受多种因素影响，并与IMPDH活性变化相关，但IMPDH与T细胞增殖的变化规律及MPA对此过程影响的个体差异机制目前尚不清楚。本课题研究中国肝移植患者外周血淋巴细胞内MPA药动学个体差异及其与血浆中MPA的相关性；患者IMPDH1、IMPDH2基因多态性对IMPDH活性变异的影响；采用流式细胞技术检测动物模型及肝移植患者体内T细胞增殖及表面抗原表达水平；采用非线性药动学法(NONMEM)建立MPA与IMPDH活性及T细胞增殖的PK/PD模型，定量分析不同调控因素对移植患者药效的影响，阐明MPA药效学个体差异的机制，为中国移植患者合理使用MPA奠定基础。

采用LC-MS/MS法分析中国肾移植患者外周血淋巴细胞(PBMC)内MPA及其他免疫抑制剂浓度，发现PBMC中MPA个体变异相对较小，而PBMC内MPA暴露水平与血浆中MPA相关；同时采用LC-MS/MS法分析PBMC中XMP浓度，作为患者IMPDH活性的标志物，肾移植患者MPA的药动与药效过程相关，IMPDH可以作为药效的生物标志物。通过小鼠皮肤移植模型，发现不同时间T细胞增殖及表面抗原表达水平与MPA体内过程存在一定相关性。转运体与IMPDH基因多态性对MPA的药动与药效均有影响。肾移植患者中与肝肠循环相关的ABCC2 C24T携带T突变基因组的AUC0-12h值均低于野生纯合子基因组(P=0.060，P=0.002)。IMPDH I 的G125A、IMPDH II的T3757C突变型患者的服用MPA后的AEC0-12h高于野生型，可部分解释IMPDH活性水平的个体差异。采用非线性药动学法(NONMEM)建立肝移植与肾移植患者MPA的群体药动学，并初步建立了MPA与IMPDH活性及T细胞增殖的PK/PD模型，定量分析不同调控因素对移植患者药效的影响，阐明MPA药效学个体差异的机制，为中国移植患者合理使用MPA提供新的手段。