title: Influence of CYP3A5 gene polymorphisms of donor rather than recipient to tacrolimus individual dose requirement in liver transplantation.
abstract: BACKGROUND
  Tacrolimus is a widely used immunosuppressant in organ transplantation, but it is characterized by a narrow therapeutic index and high interindividual variations of its pharmacokinetics. Tacrolimus is a substrate for CYP3A. It has been conjectured that CYP3A5 polymorphism is associated with tacrolimus pharmacokinetic variations. The objective of this study was to evaluate the contribution of polymorphisms of the donor and recipient CYP3A5 gene on tacrolimus disposition in liver transplantation.
  
  
  METHODS
  Fifty-three liver transplant recipients treated with tacrolimus were enrolled in this study. Tacrolimus dosage and blood trough concentration were investigated at 1 week, 2 weeks, and 1 month after transplantation. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was applied to determine the genotype of CYP3A5 gene.
  
  
  RESULTS
  The concentration/dose (C/D) ratios in patients with *1/*1(*1/*3) genotype donor were significantly lower than in patients with *3/*3 genotype donor at 2 weeks (P = 0.036) and 1 month (P = 0.021), but not at 1 week posttransplantation. Combination analysis showed that such significance still existed between CYP3A5 expressor group and nonexpressor group for both donor and recipient genotype. Also differences of C/D ratio between CYP3A5 expressor and nonexpressor donors in nonexpressor recipients were larger than those between recipients in nonexpressor donors.
  
  
  CONCLUSIONS
  The large interindividual variation of tacrolimus dose requirement is influenced by the metabolic activity of CYP3A5. Polymorphisms of the donor CYP3A5 gene seem to contribute more to such variation than the recipient. A larger population and further studies are needed to explore the exact mechanisms for tacrolimus pharmacokinetics.
authors.affiliation: Key Lab of Combined Multi-organ Transplantation, Ministry of Public Health, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
authors.forename: Songfeng
authors.initials: S
authors.lastname: Yu
authors.forename: Lihua
authors.initials: L
authors.lastname: Wu
authors.forename: Jing
authors.initials: J
authors.lastname: Jin
authors.forename: Sheng
authors.initials: S
authors.lastname: Yan
authors.forename: Guoping
authors.initials: G
authors.lastname: Jiang
authors.forename: Haiyang
authors.initials: H
authors.lastname: Xie
authors.forename: Shusen
authors.initials: S
authors.lastname: Zheng
mesh_terms: D000328:Adult; D000368:Aged; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005838:Genotype; D006801:Humans; D016031:Liver Transplantation / Q000276:immunology; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D012189:Retrospective Studies; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D014019:Tissue Donors
chemical_list: D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus