CYP3A5基因多态性对他克莫司血药浓度的影响  

Effect of CYP3A5 genetic polymorphisms on the blood concentration of tacrolimus

作　　者：陈艳梅[1] 李英[2] 韩志友[3] 武云涛[1] 董斌[3] 迟艳青[2] 

机构地区：[1]解放军北京军区总医院干一科,北京市100700 [2]河北医科大学第三医院肾内科,河北省石家庄市050051 [3]北京中医药大学东直门医院泌尿科,北京市100701

出　　处：《中国组织工程研究与临床康复》2008年第31期6055-6059,共5页Journal of Clinical Rehabilitative Tissue Engineering Research

摘　　要：背景：他克莫司属大环内酯类抗生素，具有很强的免疫抑制活性。对预防。肾移植后急性排斥反应、逆转急性排斥反应和慢性排斥反应等具有良好的疗效。但他克莫司治疗窗窄，不同的患者对他克莫司的代谢存在很大的个体差异。目的：探讨细胞色素P4503A5（CYP3A5）基因多态性对他克莫司血药浓度的影响，以期发现他克莫司在不同个体间吸收、代谢差异的基因背景，建立个体化用药的药物代谢遗传学监控体系。设计、时间及地点：病例对照观察，于2006—09／2008-03在北京中医药大学附属东直门医院。肾移植中心和解放军第二炮兵总医院临床药理中心完成。对象：选择北京东直门医院和解放军北京军区总医院正在随访的肾移植术后6个月以上稳定期患者62例，男34例，女28例，年龄25～68岁，体质量45～86妇。同期汉族健康献血者92名为正常对照组，年龄1847岁，男49名，女43名。方法：患者均使用他克莫司＋霉酚酸酯＋强的松三联免疫抑制治疗，调整剂量使他克莫司血药浓度在5-81μg/L左右，2次／d。除1例患者由服用环孢素A切换为他克莫司1年外，其他患者均肾移植后即服用他克莫司，持续半年以上。主要观察指标：①用偏振荧光免疫法测定无影响条件下3次他克莫司全血谷浓度指标。②监测血常规、肝。肾功能、血糖等生化指标。③聚合酶链反应方法扩增CYP3A5^＊3目的基因片段，直接测序的方法检测CYP3A5^＊3的多态性。④比较不同基因型之间他克莫司的浓度／剂量比的差异。结果：CYP3A5^＊3基因6986A→G中，^＊1／^＊1型为6例（9．7％），^＊1／^＊3型为26例（41．9％），^＊3／^＊3型为30例（48．4％）。^＊1／^＊1型和^＊1／^＊3型患者的他克莫司浓度／剂量比明显低于^＊3／^＊3型的患者（P均〈0．01），^＊1／^＊1型纯合子的血药浓度略低于^＊1／^�BACKGROUND： Tacrolimus is a macrolide with potent immunosuppressive effects. It has been successfully used as a prophylactic and rescued the immunosuppressant for acute and chronic rejections following renal transplantation. However, it has a narrow window of therapeutic dosage range, and the pharmacokinetic characteristics of tacrolimus are subject to high interpatient variations. OBJECTIVE： To investigate the effect of cytochrome P450 3A5 （CYP3A5^＊3） polymorphism on the blood concentration of tacrolimus, to detect the genetic background of interindividual variations for tacrolimus absorption and metabolism, and to establish the monitoring system of pharrnocokinetics in renal transplant patients. DESIGN, TIME AND SETTING： A case control observation was performed in the Kidney Transplantation Center, Dongzhimen Hospital Attached to Beijing University of Traditional Chinese Medicine and the Clinical Pharmacology Center, Second Artillery Forces General Hospital of Chinese PLA （Beijing, China） between September 2006 and March 2008. PARTICIPANTS： A total of 62 renal transplant patients were recruited from Beijing Dongzhimen Hospital and General Hospital of Beijing Military Area Command of Chinese PLA, including 34 males and 28 females, aged 25-68 years and weighing 45-86 kg. Meanwhile, 92 healthy Hans blood donors of 18-47 years old were taken as the control groups, comprising 49 males and 43 females. METHODS： Sixty-two patients received the triple immunosuppressive therapy of tacrolimus, mycophenolate and prednisone. By dose adjustment, the blood concentration of tacrolimus was 5-8μ g/L, two time a day. One patient was administrated with ciclosporin for one year and continued to administrate tacrolimus, while other patients were processed into the tacrolimus regimen for more than 6 months after renal transplantation. MAIN OUTCOME MEASURES： Tacrolimus trough concentration was measured by fluorescence polarization immunoassay and the concentration/dose ratio was determined three times

关 键 词：细胞色素P450酶系统 多态现象 免疫抑制剂 血药浓度 肾移植 

分 类 号：R617[医药卫生—外科学]