title: Effects of combinational CYP3A5 6986A>G polymorphism in graft liver and native intestine on the pharmacokinetics of tacrolimus in liver transplant patients: a meta-analysis.
abstract: BACKGROUND
  Many studies have reported reduced tacrolimus dose-adjusted exposure in individuals expressing the CYP3A5*1 allele. A meta-analyses of the current data may help characterize the extent of impact this polymorphism has on tacrolimus pharmacokinetics in adult liver transplant recipients and whether donor or recipient genotype is the most influential factor.
  
  
  METHODS
  Structured searches, of studies that evaluated the association between CYP3A5*1 allele and tacrolimus pharmacokinetics in adult liver transplant recipients, were conducted using Embase and Medline. A meta-analysis comparing tacrolimus daily dose, trough concentrations (C0), and dose-adjusted trough concentrations (C0/dose) across the donor and recipient genotype pairs was conducted using a random effects model.
  
  
  RESULTS
  Eight studies, involving a total of 694 adult liver transplant recipients, were included. Dose-adjusted tacrolimus trough concentrations were significantly lower in those in whom the donor or recipient expressed a *1 allele compared with those in whom neither the donor nor recipient expressed this allele at 7 days and 2, 3, 6, and 12 months after transplant [standardized mean differences between expressers and nonexpressers of -1.98, -2.12, -2.39, -3.68, and -3.26 (ng/mL)/(mg·kg·d), respectively].
  
  
  CONCLUSIONS
  Results of the meta-analysis demonstrated that, in adult liver transplant patients, CYP3A5 expression in either the donor or recipient resulted in a need for a higher mean tacrolimus daily dose to achieve the target drug exposure. In the immediate posttransplant period, recipient expression of a CYP3A5*1 allele seemed to have the greatest influence on tacrolimus pharmacokinetics with donor expression of a CYP3A5*1 allelle possibly becoming more important with increasing time after transplant.
authors.affiliation: *Department of Pharmacology and Toxicology, Faculty of Medicine, University of Antioquia, Medellín, Colombia; †Department of Pharmacology, Faculty of Pharmacy and University of Buenos Aires, Buenos Aires, Argentina; and ‡Pharmacy Australia Centre of Excellence, School of Pharmacy, University of Queensland, Brisbane, Australia.
authors.forename: Jefferson A
authors.initials: JA
authors.lastname: Buendia
authors.forename: Guillermo
authors.initials: G
authors.lastname: Bramuglia
authors.forename: Christine E
authors.initials: CE
authors.lastname: Staatz
mesh_terms: D000328:Adult; D000483:Alleles; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005838:Genotype; D006084:Graft Rejection / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007422:Intestines / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000601:surgery; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D016559:Tacrolimus / Q000493:pharmacokinetics*; D014019:Tissue Donors
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus