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Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients: a population pharmacokinetic analysis
Zuo, Xiao-cong1; Ng, Chee M.6; Barrett, Jeffrey S.6; Luo, Ai-jing2; Zhang, Bi-kui1; Deng, Chen-hui3; Xi, Lan-yan1; Cheng, Ke4; Ming, Ying-zi4; Yang, Guo-ping1; Pei, Qi1; Zhu, Li-jun4; Yuan, Hong1; Liao, Hai-qiang1; Ding, Jun-jie5; Wu, Di6; Zhou, Ya-nan1; Jing, Ning-ning1; Huang, Zhi-jun1
关键词CYP3A4*1G CYP3A5*3 hematocrit population pharmacokinetics renal transplantation tacrolimus
刊名PHARMACOGENETICS AND GENOMICS
2013-05-01
DOI10.1097/FPC.0b013e32835fcbb6
23期:5页:251-261
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Biotechnology & Applied Microbiology ; Genetics & Heredity ; Pharmacology & Pharmacy
研究领域[WOS]Biotechnology & Applied Microbiology ; Genetics & Heredity ; Pharmacology & Pharmacy
关键词[WOS]GENETIC POLYMORPHISMS ; BAYESIAN-ESTIMATION ; ABCB1 ; CYCLOSPORINE ; MODEL ; CYP3A4-ASTERISK-18B ; CYP3A5-ASTERISK-3 ; ASSOCIATION ; DILTIAZEM ; GENOTYPES
英文摘要

Objective Tacrolimus is used clinically for the long-term treatment of antirejection of transplanted organs in liver and kidney transplant recipients, although dose optimization is poorly managed. The aim of this study was to examine the association between tacrolimus pharmacokinetic variability and CYP3A4 and CYP3A5 genotypes by a population pharmacokinetic analysis based on routine drug monitoring data in adult renal transplant recipients.

Materials and methods Trough tacrolimus concentrations were obtained from 161 adult kidney transplant recipients after transplantation. The population pharmacokinetic analysis was carried out using the nonlinear mixed-effect modeling software NONMEM version 7.2. The CYP3A4*1G and CYP3A5*3 genetic polymorphisms from the patients studied 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 two-fold higher in kidney transplant patients with higher enzymatic activity of CYP3A5*1 and CYP3A4*1G (with the CYP3A5*1/*1 or *1/*3 and CYP3A4*1/*1G or CYP3A4*1G/*1G) compared with those with lower enzymatic activity (CYP3A5*3/*3 and CYP3A4*1/*1).

Conclusion This is the first study to extensively determine the effect of CYP3A4*1G and CYP3A5*3 genetic polymorphisms and hematocrit value on tacrolimus pharmacokinetics in Chinese renal transplant recipients. The findings suggest that CYP3A5*3 and CYP3A4*1G polymorphisms and hematocrit are determinant factors in the apparent clearance of tacrolimus. The initial dose design is mainly based on CYP3A5 and CYP3A4 genotypes as well as hematocrit. This result may also be useful for maintenance tacrolimus dose optimization and may help to avoid fluctuating tacrolimus levels and improve the efficacy and tolerability of tacrolimus in kidney transplant recipients. Pharmacogenetics and Genomics 23:251-261 (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

语种英语
WOS记录号WOS:000317399000001
项目编号81102512 ; 2011CB512001 ; 20110162120023 ; 2010WK2006
资助机构National Natural Science Foundation of China ; National Basic Research Program of China ; Ministry of Education of China ; International Scientific and Technological Cooperation Project of Hunan
引用统计
被引频次:42[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/66145
专题北京大学药学院
作者单位1.Cent S Univ, Xiangya Hosp 3, Clin Pharm & Pharmacol Res Inst, Changsha 410013, Hunan, Peoples R China
2.Key Lab Med Informat Res Hunan Higher Educ, Changsha, Hunan, Peoples R China
3.Peking Univ, Hlth Sci Ctr, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs,Dept Pharmaceu, Beijing 100871, Peoples R China
4.Cent S Univ, Xiangya Hosp 3, Dept Transplantat, Changsha 410013, Hunan, Peoples R China
5.Fudan Univ, Childrens Hosp, Dept Pharm, Shanghai 200433, Peoples R China
6.Childrens Hosp Philadelphia, Clin Pharmacol & Therapeut Div, Lab Appl PK PD, Philadelphia, PA 19104 USA
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GB/T 7714
Zuo, Xiao-cong,Ng, Chee M.,Barrett, Jeffrey S.,et al. Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients: a population pharmacokinetic analysis[J]. PHARMACOGENETICS AND GENOMICS,2013,23(5):251-261.
APA Zuo, Xiao-cong.,Ng, Chee M..,Barrett, Jeffrey S..,Luo, Ai-jing.,Zhang, Bi-kui.,...&Huang, Zhi-jun.(2013).Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients: a population pharmacokinetic analysis.PHARMACOGENETICS AND GENOMICS,23(5),251-261.
MLA Zuo, Xiao-cong,et al."Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients: a population pharmacokinetic analysis".PHARMACOGENETICS AND GENOMICS 23.5(2013):251-261.
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