title: CYP3A4*22 and CYP3A combined genotypes both correlate with tacrolimus disposition in pediatric heart transplant recipients.
abstract: BACKGROUND
  Tacrolimus metabolism depends on CYP3A4 and CYP3A5. We aimed to determine the relationship between the CYP3A4*22 polymorphism and combined CYP3A genotypes with tacrolimus disposition in pediatric heart transplant recipients.
  
  
  METHODS
  Sixty pediatric heart transplant recipients were included. Tacrolimus doses and trough concentrations were collected in the first 14 days post-transplantation. CYP3A phenotypes were defined as extensive (CYP3A5*1 + CYP3A4*1/*1 carriers), intermediate (CYP3A5*3/*3 + CYP3A4*1/*1 carriers) or poor (CYP3A5*3/*3 + CYP3A4*22 carriers) metabolizers.
  
  
  RESULTS
  CYP3A4*22 carriers needed 30% less tacrolimus (p = 0.016) to reach similar target concentrations compared with CYP3A4*1/*1 (n = 56) carriers. Poor CYP3A metabolizers required 17% (p = 0.023) less tacrolimus than intermediate and 48% less (p < 0.0001) than extensive metabolizers. Poor metabolizers showed 18% higher dose-adjusted concentrations than intermediate (p = 0.35) and 193% higher than extensive metabolizers (p < 0.0001).
  
  
  CONCLUSIONS
  Analysis of CYP3A4*22, either alone or in combination with CYP3A5*3, may help towards individualization of tacrolimus therapy in pediatric heart transplant patients.
authors.affiliation: Erasmus MC Sophia Children's Hospital, Department of Pediatric Surgery & Intensive Care, Dr Molewaterplein 60, 3015 GJ Rotterdam, The Netherlands.
authors.forename: Violette M G J
authors.initials: VM
authors.lastname: Gijsen
authors.forename: Ron Hn
authors.initials: RH
authors.lastname: van Schaik
authors.forename: Laure
authors.initials: L
authors.lastname: Elens
authors.forename: Offie P
authors.initials: OP
authors.lastname: Soldin
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Soldin
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
authors.forename: Saskia N
authors.initials: SN
authors.lastname: de Wildt
mesh_terms: D000483:Alleles; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000235:genetics; D005838:Genotype; D016027:Heart Transplantation; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D008297:Male; D011110:Polymorphism, Genetic; D012189:Retrospective Studies; D016559:Tacrolimus / Q000008:administration & dosage*; D014019:Tissue Donors
chemical_list: D007166:Immunosuppressive Agents; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus