CYP3A5基因型对中国肾移植术后患者体内他克莫司缓释剂型药动学参数的影响  

Impact of CYP3A5 genetic polymorphism on modified releasing tacrolimus pharmacokinetics in Chinese renal transplant recipients

作　　者：陈攀[1] 傅茜[2] 李晶洁[3] 孙萍萍[1] 邓蓉蓉[1] 李军[2] 刘晓曼[4] 王洪阳[2] 黄民[4] 陈孝[1] 王长希[2] 

机构地区：[1]中山大学附属第一医院药学部临床药学室,广东广州510655 [2]中山大学附属第一医院器官移植中心,广东广州510655 [3]中山大学附属第六医院生殖医学中心,广东广州510655 [4]中山大学临床药理研究所,广东广州510080

出　　处：《中国药理学通报》2016年第11期1592-1595,共4页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No 81503156);广东省自然科学基金博士启动项目(No 2014A030310096);广东省公益基金项目(No 2016A020218006)

摘　　要：目的 研究CYP3A5基因型对中国肾移植术后患者体内他克莫司缓释剂型药动学参数的影响。方法 采用化学发光免疫法检测20例肾移植术后患者在服用缓释（10例）和普通剂型（10例）他克莫司后的全血浓度;采用聚合酶链反应-限制性片段长度多态法检测服用缓释剂型他克莫司患者的CYP3A5基因型;缓释剂型组检测0-24h的11个时间点的血药浓度,而普通剂型检测0-12h内的10个时间点的血药浓度。结果无剂量校正的缓释剂型组的AUC0-24h为普通剂型组AUC0-12h的1.78倍,有剂量校正的缓释剂型组的C0为普通剂型的60%,其余药动学参数差异无显著性;缓释剂型中慢代谢型组的Cmax、AUC0-24h和C0分别为快代谢型组的1.75、1.96、2.49倍（无剂量校正）以及1.80、2.34和2.64倍（有剂量校正）;缓释剂型组的C0与AUC0-24h的相关性良好。结论 他克莫司普通剂型转换至缓释剂型时应该注意上调给药剂量,同时缓释剂型应结合CYP3A5的基因型检测,确保C0值在治疗窗范围内。Aim To investigate the impact of CYP3A5 genetic polymorphism on modified releasing tacrolimus pharmacokinetics in Chinese stable renal transplant recipients. Methods Pharmacokinetics of once daily-tacrolimus( tac-q. d.) and twice daily-tacrolimus( tac-b.i. d.) were determined by CLIA,CYP3A5 genotype was measured by PCR-RFLP. Each 10 patients receiving tac-q. d. and tac-b. i. d. respectively were enrolled,and each 5 patients receiving tac-q. d. were matched to poor metabolizer( PM) and extensive metabolizer( EM) group respectively according to CYP3A5 genotypes. Results AUC_(0 ~ 24 h)for tac-q. d.was 1. 78 folds higher than AUC_(0 ~ 12 h)for tac-b. i. d.,and dose-adjusted C_0 was 40% lower for tac-q. d. than for tac-b. i. d. There were no significant differences for other parameters between the two groups; Cmax,AUC_(0 ~ 24 h)and C_0 were 1. 75,1. 96 and 2. 49 folds higher for PM than for EM,and dose-adjusted Cmax,AUC_(0 ~ 24 h)and C_0 were 1. 80,2. 34 and 2. 64 folds higher for PM than for EM. There were good correlations between AUC_(0 ~ 24 h)and C_0 for tac-q. d. Conclusion Conversion from tac-b. i. d. to tac-q. d. results in requirement of increased tacrolimus dose and detection of CYP3A5 genotype,which is necessary for ensuring C_0 in the range of therapeutic window.

关 键 词：他克莫司 缓释剂型 肾移植 CYP3A5 药代动力学 基因多态性 免疫抑制剂 

分 类 号：R345.99[医药卫生—基础医学] R392.2