肾移植受者CYP3A5＊3和CYP3A4＊18B对他克莫司药动学的影响  

Effect of CYP3A5 and CYP3A4 on pharmacokinetics of Tacrolimus in renal transplantation recipients

作　　者：林玲[1] 宋文利[2] 沈中阳[2] 张弋[2] 

机构地区：[1]天津医科大学一中心临床学院,300192 [2]天津市第一中心医院

出　　处：《中华器官移植杂志》2012年第4期220-224,共5页Chinese Journal of Organ Transplantation

基　　金：天津市卫生局科技基金（07KY27）;天津市卫生局攻关课题（11KG102）

摘　　要：目的探讨肾移植受者细胞色素P450酶（CYP）3A5＊3、CYP3A4＊18B和CYP3A5-CYP3A4单倍型对他克莫司（Tac）药动学的影响。方法采用DNA测序法检测61例肾移植受者CYP3A5＊3和CYP3A4＊18B基因型。酶联免疫吸附试验测定受者的血Tac浓度，比较术后14d和1、2、3个月时不同基因型受者之间血Tac浓度谷值（G0）、Tac剂量（D）及浓度／剂量（G0／D）的差异。结果61例中，CYP3A5＊3和CYP3A4＊18B等位基因突变频率分别为74．6%和26．2％。当CYP3A5表达（＊1／＊1＋＊1／＊3）者的D是CYP3A5未表达（＊3／＊3）者的1．3～1．6倍时，未表达者的G，却是表达者的1．1～1．5倍，G，／D是表达者的1．8～2．4倍。CYP3A4＊18B（＊1／＊18B及＊1813／＊18B）基因型者的D是CYP3A4＊1／＊1基因型者的1．2～1．5倍时，＊1／＊1基因型者的G，是＊18B基因型者的1．2～1．4倍，G0／D是＊18B基因型者的1．5～1．8倍。当CYP3A5-CYP3A4（A～AA）者的D是CYP3A5-CYP3A4（GpGG）者的1．3～1．7倍时，GG-GG的G，是AA-AA的1．5～2倍，G0／D是AA-AA的2．5～3倍。当受者G0／D分别位于中位数上下时，CYP3A5、CYP3A4不同基因型和CYP3A5-CYP3A4不同单倍型受者的分布差异较大。结论肾移植受者CYP3A5＊3和CYP3A4＊18B基因多态性对Tac的药动学有显著影响，对CYP3A5-CYP3A4单倍型的分析比单独考虑一种基因型影响更为显著。Objective To retrospectively investigate the effects of CYP3A5 ＊ 3, CYP3A4 ＊ 18B and CYP3A5-CYP3A4 phenotype on the G0, D and G＊/D of tacrolimus （Tae） in renal transplantation recipients. Methods The CYP3A5 ＊ 3 and CYP3A4 ＊ 18B genotypes of the 61 patients were detected by DNA direct sequencing, and the G0 was detected by ELISA. The differences of G0, D and G0/D on the day 14, and month 1, 2 and 3 after transplantation were compared among different genotypes of recipients treated with Tac. Results The frequency of the CYP3A5 ＊ 3 and CYP3A4 ＊ 1 8B was 74. 6% and 26. 2% respectively. When the D of the recipients with CYP3A5 ＊ 1 （ ＊ 1/＊ 1 ＋ ＊ 1/＊ 3） was 1.3-1.6 times to the CYP3A5 ＊ 3/＊ 3, the G0 of ＊ 3/＊ 3 group was 1.1-1.5 times to the ＊ 1 group, and the G＊/D was 1.8 2. 4 times to the CYP3A5 ＊ 1. For CYP3A4, the D of CYP3A4 ＊ 18B group （ ＊ 1/＊- 18B＋ ＊ 18B/＊ 18B） was 1. 2-1.5 times to the CYP3A5 ＊ 1/＊ 1, but the G＊ of 1/＊ 1 was 1.2 1.4 times to the ＊ 18B,the G0/D was 1.5-1.8 times to the ＊ 18B. For the CYP3A5 CYP3A4 phenotype, the D of the recipients with AA-AA was 1.3-1.7 times to the CX3-GG, the G, of GG-GG was 1.5-2 times to the AA-AA, the G0/D of the recipients with GG-GG- was 2. 5 3 times to the AA-AA. In the recipients with G0/D above or below the median of G0/D, the distribution of CYP3A5, CYP3A4 and CYP3AS-CYP3A4 phenotypes was different significantly. Conclusion There is a significant correlation between the CYP3A5, CYP3A4 and pharmacokinetics of Tac. It＇s more powerful evaluating the CYP3A5-CYP3A4 phenotype rather than just one genotype of the recipients. So detecting the CYP3A5 ＊ 3 and CYP3A4 ＊ 18B genotypes prior to transplantation is meaningful for us to determine an appropriate initial and long-time dosage of Tac.

关 键 词：肾移植 他克莫司 药代动力学 细胞色素P450 CYP3A5 细胞色素P450 CYP3A4 基因多态性 

分 类 号：R657.3[医药卫生—外科学]