title: The genetic polymorphisms of POR*28 and CYP3A5*3 significantly influence the pharmacokinetics of tacrolimus in Chinese renal transplant recipients.
abstract: OBJECTIVE
  The aims of this study were to assess the influence of the polymorphism of cytochrome P450 oxidoreductase (POR) as well as other relevant genes (CYP3A4, CYP3A5, ABCB1) on individual variability of tacrolimus pharmacokinetics and perform population pharmacokinetic analysis of tacrolimus in Chinese renal transplant recipients.
  
  
  METHODS
  Tacrolimus trough whole blood concentrations and clinical details were retrospectively collected from 83 renal recipients. CYP3A4*1G, CYP3A5*3, and ABCB1 C3435T were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), POR*28 and CYP3A4*22 were genotyped by sequencing method. Population pharmacokinetic analysis was performed using NONMEM program.
  
  
  RESULTS
  The significant influences of CYP3A5*3, CYP3A4*1G, and POR*28 polymorphisms on tacrolimus dose-adjusted trough concentrations (C0/D) were observed in 83 renal recipients. Subgroup analysis showed that POR*28 polymorphisms significantly decreased tacrolimus C0/D by 1.50 - 1.84-fold (p < 0.05) in patients who were CYP3A5 expressers (CYP3A5*1 carriers, n = 46), while similar results could not be obtained from CYP3A5 non-expressers (CYP3A5*3/*3 carriers, n = 37). Additionally, population pharmacokinetic analysis identified that the combined genotype of CYP3A5-POR was the only covariant for the apparent clearance of tacrolimus (CL/F).
  
  
  CONCLUSIONS
  The study demonstrated that the POR*28 C>T mutation could decrease the C0/D of tacrolimus in renal recipients who were CYP3A5 expressers. The population pharmacokinetic model showed that the combined genotype of CYP3A5-POR was associated with the CL/F of tacrolimus which might provide references for personalized use of tacrolimus in clinic.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Zhang
authors.forename: Shuai-Bing
authors.initials: SB
authors.lastname: Liu
authors.forename: Ling
authors.initials: L
authors.lastname: Xue
authors.forename: Xiao-Liang
authors.initials: XL
authors.lastname: Ding
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Li-Yan
authors.initials: LY
authors.lastname: Miao
mesh_terms: D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D016559:Tacrolimus / Q000493:pharmacokinetics*
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D009251:NADPH-Ferrihemoprotein Reductase; D016559:Tacrolimus