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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-conga; Ng, Chee M.f; Barrett, Jeffrey S.f; Luo, Ai-jingb; Zhang, Bi-kuia; Deng, Chen-huic; Xi, Lan-yana; Cheng, Ked; Ming, Ying-zid; Yang, Guo-pinga; Pei, Qia; Zhu, Li-jund; Yuan, Honga; Liao, Hai-qianga; Ding, Jun-jiee; Wu, Dif; Zhou, Ya-nana; Jing, Ning-ninga; Huang, Zhi-juna

Pharmacogenetics and Genomics: May 2013 - Volume 23 - Issue 5 - p 251–261
doi: 10.1097/FPC.0b013e32835fcbb6

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.

aClinical Pharmacy and Pharmacology Research Institute, The Third Xiangya Hospital of Central South University

bKey Laboratory of Medical Information Research in Hunan Higher Education, Changsha

cState Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing

dDepartment of Transplantation, The Third Xiangya Hospital of Central South University, Changsha

eDepartment of Pharmacy, Children’s Hospital of Fudan University, Shanghai, China

fLaboratory for Applied PK/PD, Clinical Pharmacology & Therapeutics Division, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA

Correspondence to Hong Yuan, PhD, Clinical Pharmacy and Pharmacology Research Institute, The Third Xiangya Hospital of Central South University, Changsha 410013, China Tel: +86 731 88618325; fax: +86 731 88618455; e-mail:

Received October 13, 2012

Accepted February 4, 2013

© 2013 Lippincott Williams & Wilkins, Inc.