title: Pharmacogenetics of calcineurin inhibitors in Brazilian renal transplant patients.
abstract: OBJECTIVE
  Polymorphisms in the CYP3A5 and ABCB1 genes have been investigated as modulators of the pharmacokinetics and clinical effects of cyclosporine (CSA) and tacrolimus (TAC) in European, North American and Asian populations, with controversial results. The extensive variation in worldwide frequency distribution of CYP3A5 and ABCB1 polymorphisms is a caveat against the extrapolation of these data to the heterogeneous and admixed Brazilian population. We investigated the effect of CYP3A5 and ABCB1 polymorphisms on CSA and TAC dose-adjusted trough concentration (C₀/dose) in Brazilian renal transplant recipients, during the first 3 months post-transplantation.
  
  
  METHODS
  Patients receiving CSA (n = 150) or TAC (n = 151) were genotyped for CYP3A5*3 (rs776746, 6986A>G), *6 (rs10264272, 14690G>A) and *7 (rs41303343, 27131-27132insT) and for ABCB1 1236C>T (rs1128503), 2677G>T/A (rs2032582) and 3435C>T (rs1045642) polymorphisms. We explored the effects of CYP3A5 and ABCB1 polymorphisms, clinical and demographical characteristics on CSA and TAC C₀/dose under a two-step data analysis strategy by fitting a longitudinal mixed-effects model to the data; first to select the important covariates under a univariate setting and then to fit the final multivariate model.
  
  
  RESULTS
  C₀/dose of TAC was associated with the number of CYP3A5-defective alleles, in a gene-dose manner, throughout the observation period, whereas C₀/dose of CSA was associated with body surface area and prednisone dosing. No other significant associations were detected.
  
  
  CONCLUSIONS
  Individual adjustment of the initial TAC dose according to the CYP3A5 haplotypes comprising the CYP3A5*3, *6 and *7 defective alleles might prove beneficial to Brazilian renal transplant recipients and should be further investigated in prospective trials.
authors.affiliation: Divisão de Farmacologia, Coordenação de Pesquisa, Instituto Nacional de Câncer, Rio de Janeiro, RJ 20231-050, Brazil.
authors.forename: Ana
authors.initials: A
authors.lastname: Santoro
authors.forename: Claudia R
authors.initials: CR
authors.lastname: Felipe
authors.forename: Helio
authors.initials: H
authors.lastname: Tedesco-Silva
authors.forename: Jose O
authors.initials: JO
authors.lastname: Medina-Pestana
authors.forename: Claudio J
authors.initials: CJ
authors.lastname: Struchiner
authors.forename: Elida B
authors.initials: EB
authors.lastname: Ojopi
authors.forename: Guilherme
authors.initials: G
authors.lastname: Suarez-Kurtz
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000008:administration & dosage / Q000493:pharmacokinetics; D001938:Brazil; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D018628:Gene Dosage / Q000235:genetics; D056726:Genetic Association Studies; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D001379:Azathioprine; D016559:Tacrolimus