肾移植受者术后早期他克莫司用药剂量及浓度个体差异的研究

Differences of tacrolimus＇ dosage and concentration of individuals in morning periods after renal transplantation

目的探讨肾移植受者术后早期他克莫司（FK506）剂量及浓度个体差异的原因。方法肾移植术后早期采用FK506、霉酚酸酯及激素三联免疫抑制剂的受者118例，记录性别、年龄、身高，术后第3、7、14、30天分别记录体质量、FK506剂量、激素剂量、腹泻、血脂、肝功、肾功、白蛋白、血细胞比容等指标，测定每例患者细胞色素酶P450—3A5（cYP3A5）和多药耐药基因1（MDR1）3435、2677、1236位点基因多态性及不同时期FK506全血谷浓度，以FK506浓度／（剂量×体表面积）为因变量分别进行多元线性回归分析。结果多元线性回归模型的拟合度偏低，修正R2值在术后第3、7、14、30天分别为0．284、0．267、0．417、0．324。药物基因组学因素有MDR12677、MDR1 1236、MDR13435且变化剧烈，不同个体达到相同FK506浓度所需剂量突变型纯合子〈杂合子〈野生型纯合子。非药物基因组学因素在术后第3天为年龄、白蛋白和高密度脂蛋白胆固醇，第7天为白蛋白、年龄和血清肌酐，第14天为激素剂量和天冬氨酸转氨酶，上述影响因素均与FK506浓度／（剂量×体表面积）呈正相关。结论肾移植术后早期受者FK506剂量及浓度个体差异的原因主要是术后用药和受者剧烈的内环境变化，并与受者MDR1基因多态性、年龄、白蛋白、移植肾功能恢复情况、血脂和肝功能有关，术前应充分透析，尽可能改善患者一般情况，术后应当尽量避免使用对FK506吸收和代谢干扰大的药物。

Objective To study the influential factors of tacrolimus＇ dosage and concentration differences between individuals in morning periods after renal transplantation. Methods The clinical data consisted of 118 receptors in morning periods after renal transplantation, whose immune suppres- sions were tacrolimus, mycophenolate and hormone. At 3, 7, 14 and 30 d after operation, all the receptors＇ weight, dosage of tacrolimus, dosage of hormone, diarrhea, blood fat, liver function, renal function, albumn and erythrocrit were recorded respectively, and at the same time their concentrations of tacrolimus and genetic polymorphisms of CYP3A5, MDR1 3435, MDR1 2677 and MDR1 1236 were detected. Multiple linear regressions were performed. Results The fitting degrees of stepwise re- gression equations were low. At 3, 7, 14 and 30 d after operation, the adjusted R2 was 0. 284, 0. 267, 0. 417 and 0. 324, respectively. From the aspect of pharmacogenomics, the main factors rela-ted to the differences of tacrolimus＇ dosage and concentration included MDR1 2677, MDR1 1236 and MDR1 3435, which varied intensively. Age, albumn, renal function, blood fat and liver function were important factors too. Conclusions The main reasons of the differences of tacrolimus＇ dosage and concentration between individuals in morning periods after renal transplantation are medicines and changes of internal environment after operation. The genetic polymorphisms of MDR：I, age, albumn, renal function, blood fat and liver function are important factors too.