title: Effect of CYP3A5 polymorphism on the pharmacokinetics of tacrolimus and acute rejection in renal transplant recipients: experience at a single centre.
abstract: OBJECTIVE
  As a substrate of cytochrome P450 (CYP) 3A5, tacrolimus is characterised by a narrow therapeutic index and large inter-individual variability. Our objective was to determine the influence of CYP3A5 genetic polymorphisms on tacrolimus pharmacokinetics and acute rejection in Chinese renal transplant recipients.
  
  
  METHODS
  Thirty-five renal recipients treated with tacrolimus in our centre were genotyped for CYP3A5 single nucleotide polymorphisms, CYP3A5*1 (6986A) and CYP3A5*3 (6986G). These patients were divided into the following three groups: CYP3A5*1*1 homozygous carriers, CYP3A5*3*3 homozygous carriers and CYP3A5*1*3 heterozygous carriers. Doses administered at 1 week and at 1, 6 and 12 months posttransplantation were recorded. Whole blood concentration was measured using the enzyme-multiplied immunoassay technique. Biopsy-proven acute rejection episodes (BPAR) reported during the first year after transplant were obtained retrospectively.
  
  
  RESULTS
  The concentration/dose ratios of CYP3A5*3 homozygous carriers at 1 week and at 1, 6 and 12 months were significantly higher than the ratios among CYP3A5*1 carriers (CYP3A5*1*1 and CYP3A5*1*3, p < 0.05). BPAR occurred in four patients during the first month after transplant, three of whom were CYP3A5*1 carriers.
  
  
  CONCLUSIONS
  CYP3A5 genetic polymorphism is associated with the concentration/dose ratio of tacrolimus in Chinese renal recipients. Patients with CYP3A5*1*1 genotypes require higher doses of tacrolimus to achieve the target concentration and may be at risk of acute rejection soon after transplant because of inadequate immunosuppression. Screening for this polymorphism could be helpful in choosing the suitable calcineurin inhibitors and determining the suitable initial dose.
authors.affiliation: Organ Transplant Unit of the First Hospital of China Medical University, Shenyang, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Organ Transplant Unit of the First Hospital of China Medical University, Shenyang, China.
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.affiliation: Organ Transplant Unit of the First Hospital of China Medical University, Shenyang, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Meng
authors.affiliation: Organ Transplant Unit of the First Hospital of China Medical University, Shenyang, China.
authors.forename: H
authors.initials: H
authors.lastname: Liu
authors.affiliation: Organ Transplant Unit of the First Hospital of China Medical University, Shenyang, China.
authors.forename: L
authors.initials: L
authors.lastname: Yang
authors.affiliation: Organ Transplant Unit of the First Hospital of China Medical University, Shenyang, China.
authors.forename: T
authors.initials: T
authors.lastname: Xu
authors.affiliation: Organ Transplant Unit of the First Hospital of China Medical University, Shenyang, China.
authors.forename: J
authors.initials: J
authors.lastname: Yu
authors.affiliation: Organ Transplant Unit of the First Hospital of China Medical University, Shenyang, China.
authors.forename: N
authors.initials: N
authors.lastname: Zhao
authors.affiliation: Organ Transplant Unit of the First Hospital of China Medical University, Shenyang, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
mesh_terms: D000208:Acute Disease; D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D005838:Genotype; D006084:Graft Rejection / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics; D016030:Kidney Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D016559:Tacrolimus / Q000493:pharmacokinetics*; D066027:Transplant Recipients
chemical_list: D007166:Immunosuppressive Agents; D004247:DNA; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus