CYP3A4和CYP3A5基因多态性对中国成人肾移植患者他克莫司药动学影响的群体药代动力学研究

左笑丛; Chee M. Ng; Jeffrey S.Barrett; 罗爱静; 张毕奎; 邓晨辉; 席兰艳; 成柯; 明英姿; 阳国平; 裴琦; 朱利军; 袁洪; 廖海强; 丁俊杰; 吴荻; 周亚男; 荆宁宁; 黄志军

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CYP3A4 and CYP3A5 Polymorphism Effects on Tacrolimus Pharmacokinetics in Chinese Adult Renal Transplant Recipients: A Population Pharmacokinetic Analysis

首发时间：2013-05-02

ZUO Xiaocong ¹
ZUO Xiaocong,（1973-）, female, Associate Professor, main research: personalized medication.
Chee M. Ng ² Jeffrey S.Barrett ² LUO Aijing ³ ZHANG Bikui ⁴ DENG Chenhui ⁵ XI Lanyan ⁴ CHENG Ke ⁶ MING Yingzi ⁶ YANG Guoping ⁴ PEI Qi ⁴ ZHU Lijun ⁶ YUAN Hong ⁴
YUAN Hong(1948-), male，Professor, main research: cardiovascular pharmacology
LIAO Haiqiang ⁴ DING Junjie ⁷ WU Di ² ZHOU Yanan ⁴ JING Ningning ⁴ HUANG Zhijun ⁴

1、Clinical Pharmacy and Pharmacology Research Institute, The Third Xiangya Hospital of Central South University, Changsha 410013
2、Laboratory for Applied PK/PD, Clinical Pharmacology & Therapeutics Division, The Children’s Hospital of Philadelphia, Philadelphia 19019
3、Key Laboratory of Medical Information Research in Hunan Higher Education,Changsha 410013
4、Clinical Pharmacy and Pharmacology Research Institute, The Third Xiangya Hospital of Central South University,Changsha 410013
5、State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100083
6、Department of Transplantation, The Third Xiangya Hospital of Central South University, Changsha 410013
7、Department of Pharmacy, Children’s Hospital of Fudan University, Shanghai 200000

Abstract：Objective Tacrolimus is used clinically for long-term treatment of antirejection of transplanted organs in liver and kidney transplant recipients though dose optimization is poorly managed. The goal of this study was to investigate the association between tacrolimus pharmacokinetic variability and CYP3A4 and CYP3A5 genotype by a population pharmacokinetic analysis based on routine drug monitoring data in adult renal transplantation recipients. Methods Trough tacrolimus concentrations were obtained from 161 adult kidney transplant recipients post-transplantation. The population pharmacokinetic analysis was performed using the nonlinear mixed-effect modeling software NONMEM version 7.2. The CYP3A4*1G and CYP3A5*3 genetic polymorphisms from studied patients were determined by direct sequencing using a validated automated genetic analyzer. Results A one-compartment model with first-order absorption and elimination adequately described the pharmacokinetics of tacrolimus. Covariates including CYP3A5*3 and CYP3A4*1G alleles and hematocrit were retained in the final model. The apparent clearance of tacrolimus was about 2-fold higher in kidney transplant patients with CYP3A5*3 and CYP3A4*1G higher enzymatic activity (with the CYP3A5 *1/*1 or *1/*3 and CYP3A4*1/*1G or CYP3A4*1G/*1G) compared to those with lower enzymatic activity (CYP3A5 *3/*3 and CYP3A4*1/*1). Conclusion This is the first study to extensively investigate the effect of CYP3A4*1G and CYP3A5*3 genetic polymorphisms and hematocrit value on tacrolimus pharmacokinetics in renal transplantation recipients. The findings suggest that CYP3A5*3 and CYP3A4*1G polymorphisms and hematocrit are determinant factor in the apparent clearance of tacrolimus. The initial dose design is mainly based on CYP3A5 and CYP3A4 genotypes as well as hematocrit.This results may also be good for the maintenance tacrolimus dose optimization and help to avoid fluctuating tacrolimus levels and improve the efficacy and tolerability of tacrolimus in kidney transplant recipients.

keywords： CYP3A5*3 CYP3A4*1G hematocrit population pharmacokinetics tacrolimus kidney transplantation

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CYP3A4和CYP3A5基因多态性对中国成人肾移植患者他克莫司药动学影响的群体药代动力学研究

左笑丛 ¹
ZUO Xiaocong,（1973-）, female, Associate Professor, main research: personalized medication.
Chee M. Ng ² Jeffrey S.Barrett ² 罗爱静 ³ 张毕奎 ¹ 邓晨辉 ⁴ 席兰艳 ¹ 成柯 ⁵ 明英姿 ⁵ 阳国平 ¹ 裴琦 ¹ 朱利军 ⁵ 袁洪 ¹
YUAN Hong(1948-), male，Professor, main research: cardiovascular pharmacology
廖海强 ¹ 丁俊杰 ⁶ 吴荻 ² 周亚男 ¹ 荆宁宁 ¹ 黄志军 ¹

1、中南大学湘雅三医院临床药理机构，长沙 410013
2、美国费城儿童医院临床药学部应用PK/PD实验室，费城 19019
3、湖南高等教育医学信息研究重点实验室，长沙 410013
4、北京大学药学院天然药物与仿生药物国家重点实验室，北京 100083
5、中南大学湘雅三医院移植科，长沙 410013
6、复旦大学儿童医院药学部，上海 200000

摘要：目的：他克莫司在临床上常用于器官移植患者长期抗排斥治疗，但目前仍没有优化的给药方式。本研究要利用成年肾移植患者的常规药物浓度监测结果，用群体药动学的方法研究CYP3A4和CYP3A5基因型和他克莫司浓度变异之间的关系。方法：我们获得了161位肾移植术后患者的他克莫司谷浓度数据。利用非线性混合效应模型软件NONMEM7.2进行群体药动学分析。所研究患者的CYP3A4*1G和CYP3A5基因型利用全自动基因分析仪器通过直接测序获得。结果：一级吸收和消除的一室模型可以完全描述他克莫司的药动学。协变量中CYP3A4*1G、CYP3A5*3等位基因和红细胞压积进入最终模型。CYP3A5*3 和CYP3A4*1G 酶活性较高(CYP3A5 *1/*1 或*1/*3以及CYP3A4*1/*1G或CYP3A4*1G/*1G)的肾移植患者较酶活性较低的患者(CYP3A5 *3/*3 和 CYP3A4*1/*1)表观清除率高出两倍。结论：本研究第一次详细探讨CYP3A5*3以及CYP3A4*1G基因多态性和红细胞压积值对肾移植受者他克莫司药动学的影响。结果表明CYP3A5*3以及CYP3A4*1G基因多态性和红细胞压积是他克莫司表观清除率的决定因素，初始计量设计是基于CYP3A5*3以及CYP3A4*1G基因多态性以及红细胞压积值的。本研究有助于他克莫司维持剂量的优化，避免他克莫司浓度的不稳定并改善肾移植患者中他克莫司的有效性和耐受性。

关键词： CYP3A5*3 CYP3A4*1G 红细胞压积群体药动学他克莫司肾移植

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ZUO Xiaocong,Chee M. Ng,Jeffrey S.Barrett,et al. CYP3A4 and CYP3A5 Polymorphism Effects on Tacrolimus Pharmacokinetics in Chinese Adult Renal Transplant Recipients: A Population Pharmacokinetic Analysis[EB/OL]. Beijing:Sciencepaper Online[2013-05-02]. https://www.paper.edu.cn/releasepaper/content/201305-30.

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论文编号	201305-30
论文题目	CYP3A4和CYP3A5基因多态性对中国成人肾移植患者他克莫司药动学影响的群体药代动力学研究
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