title: Influence of CYP3A5 genotypes on tacrolimus dose requirement: age and its pharmacological interaction with ABCB1 genetics in the Chinese paediatric liver transplantation.
abstract: OBJECTIVE
  The purpose of the study was to evaluate the impact of single nucleotide polymorphisms (SNPs) of Cytochrome P450 (CYP) 3A5 and adenosine triphosphate-binding cassette B1 (ABCB1) genotypes on TAC pharmacokinetics in Chinese paediatric patients.
  
  
  METHODS
  A total of 136 Chinese paediatric liver recipients (R) and their donors (D) were divided into groups according to their CYP3A5 genotypes [expression of *1 allele: expressor (EX) or non-expressor (NEX)].
  
  
  RESULTS
  Both recipient and donor CYP3A5*1 alleles had impacts on the TAC pharmacokinetics after liver transplantation. EX-R/EX-D recipients required a significantly higher TAC daily dose compared with NEX-R/NEX-D (0.24 ± 0.08 vs. 0.14 ± 0.06 mg/kg/day, p < 0.01). Age was also an independent factor on TAC requirement. Compared with EX-R/EX-D, non-expressor infants or recipients over 3-years old needed < 0.2 mg/kg/day. None of the ABCB1 SNPs (1236C>T, 2677G>A/T, 3435C>T) had an impact on TAC pharmacokinetics. However, EX-R/EX-D recipients bearing the ABCB1 1236-CC genotype required a much higher TAC dose than those without this genotype (0.23 vs. 0.18 mg/kg/day, p < 0.01), who required a similar TAC dose to that of NEX-R/NEX-D children. Furthermore, EX-R/EX-D with ABCB1 1236-CC recipients exhibited an markedly higher incidence of acute rejection and transplant-related infections clinically.
  
  
  CONCLUSIONS
  CYP3A5 and ABCB1-1236 genotyping, in addition to recipient age, are necessary for establishing a more accurate TAC dosage regimen in paediatric liver recipients. We should be cautious regarding the treatment of paediatric recipients with both CYP3A5-expressor and ABCB1 1236-CC genotypes with TAC, as these patients are more susceptible to acute rejection and infection.
authors.affiliation: Department of Liver Surgery and Liver Transplantation, Ren Ji Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China.
authors.forename: T-H
authors.initials: TH
authors.lastname: Yang
authors.affiliation: Department of Liver Surgery and Liver Transplantation, Ren Ji Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Y-K
authors.initials: YK
authors.lastname: Chen
authors.affiliation: Department of Liver Surgery and Liver Transplantation, Ren Ji Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China.
authors.forename: F
authors.initials: F
authors.lastname: Xue
authors.affiliation: Department of Liver Surgery and Liver Transplantation, Ren Ji Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China.
authors.forename: L-Z
authors.initials: LZ
authors.lastname: Han
authors.affiliation: Department of Liver Surgery and Liver Transplantation, Ren Ji Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China.
authors.forename: C-H
authors.initials: CH
authors.lastname: Shen
authors.affiliation: Department of Liver Surgery and Liver Transplantation, Ren Ji Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China.
authors.forename: T
authors.initials: T
authors.lastname: Zhou
authors.affiliation: Department of Liver Surgery and Liver Transplantation, Ren Ji Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Department of Liver Surgery and Liver Transplantation, Ren Ji Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China.
authors.forename: J-J
authors.initials: JJ
authors.lastname: Zhang
authors.affiliation: Department of Liver Surgery and Liver Transplantation, Ren Ji Hospital, School of Medicine Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Xia
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis / Q000235:genetics; D000328:Adult; D002675:Child, Preschool; D002681:China / Q000453:epidemiology; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis / Q000235:genetics*; D004247:DNA / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005786:Gene Expression Regulation; D005838:Genotype; D006084:Graft Rejection / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D015994:Incidence; D007223:Infant; D016031:Liver Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies; D016559:Tacrolimus / Q000008:administration & dosage*; D013997:Time Factors; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D004247:DNA; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus