title: Effects of CYP3A4 and CYP3A5 polymorphisms on tacrolimus pharmacokinetics in Chinese adult renal transplant recipients: a population pharmacokinetic analysis.
abstract: 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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors: Clinical Pharmacy and Pharmacology Research Institute, The Third Xiangya Hospital of Central South University, Beijing, China.
authors: Xiao-cong
authors: XC
authors: Zuo
authors: Chee M
authors: CM
authors: Ng
authors: Jeffrey S
authors: JS
authors: Barrett
authors: Ai-jing
authors: AJ
authors: Luo
authors: Bi-kui
authors: BK
authors: Zhang
authors: Chen-hui
authors: CH
authors: Deng
authors: Lan-yan
authors: LY
authors: Xi
authors: Ke
authors: K
authors: Cheng
authors: Ying-zi
authors: YZ
authors: Ming
authors: Guo-ping
authors: GP
authors: Yang
authors: Qi
authors: Q
authors: Pei
authors: Li-jun
authors: LJ
authors: Zhu
authors: Hong
authors: H
authors: Yuan
authors: Hai-qiang
authors: HQ
authors: Liao
authors: Jun-jie
authors: JJ
authors: Ding
authors: Di
authors: D
authors: Wu
authors: Ya-nan
authors: YN
authors: Zhou
authors: Ning-ning
authors: NN
authors: Jing
authors: Zhi-jun
authors: ZJ
authors: Huang
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D002681:China; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000188:drug therapy / Q000235:genetics*; D006400:Hematocrit; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016030:Kidney Transplantation; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects / Q000235:genetics; D008875:Middle Aged; D011110:Polymorphism, Genetic; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus