title: Relationship of CYP3A5 genotype and ABCB1 diplotype to tacrolimus disposition in Brazilian kidney transplant patients.
abstract: OBJECTIVE
  Tacrolimus (TAC) is one of the most successful immunosuppressive drugs in transplantation. Its pharmacokinetics (PK) and pharmacogenetics (PG) have been extensively studied, with many studies showing the influence of CYP3A5 on TAC metabolism and bioavailability. However, data concerning the functional significance of ABCB1 polymorphisms are uncertain due to inconsistent results. We evaluated the association between ABCB1 diplotypes, CYP3A5 polymorphisms and TAC disposition in a cohort of Brazilian transplant recipients.
  
  
  METHODS
  Individuals were genotyped for the CYP3A5*3 allele and ABCB1 polymorphisms (2677G>A/T, 1236C>T, 3435C/T) using a TaqMan® PCR technique. Diplotypes were analyzed for correlation with the TAC dose-normalized ratio (Co : dose).
  
  
  RESULTS
  We genotyped 108 Brazilian kidney recipients for CYP3A5 (11% CYP3A5*1/*1; 31% CYP3A5*1/*3 and 58% CYP3A5*3/*3) and ABCB1 haplotypes (42% CGC/CGC; 41% GCG/TTT and 17% TTT/TTT). Homozygous subjects for the CYP3A5*3 allele or carriers of the ABCB1 TTT/TTT diplotype showed a higher Co : dose ratio compared with wild type subjects [median (interquartile range) 130.2 (97.5-175.4) vs. 71.3 (45.6-109.0), P < 0.0001 and 151.8 (112.1-205.6) vs. 109.6 (58.1-132.9), P = 0.01, respectively]. When stratified for the CYP3A5*3 group, ABCB1 TTT/TTT individuals showed a higher Co : dose ratio compared with non-TTT/TTT individuals [167.8 (130.4-218.0) vs. 119.4 (100.2-166.3), P = 0.04]. Multivariate linear regression analysis showed that the effects of CYP3A5 polymorphisms and ABCB1 diplotypes remained significant after correction for confounding factors.
  
  
  CONCLUSIONS
  CYP3A5 is the major enzyme responsible for the marked interindividual variability in TAC PK, but it cannot be considered alone when predicting dose adjustment because ABCB1 diplotypes also affect TAC disposition, showing independent and additive effects on the TAC dose-normalized concentration.
authors: Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Av. Bandeirantes, 3900, 14049-900, Ribeirão Preto, São Paulo, Brazil.
authors: Diego Alberto C
authors: DA
authors: Cusinato
authors: Riccardo
authors: R
authors: Lacchini
authors: Elen A
authors: EA
authors: Romao
authors: Miguel
authors: M
authors: Moysés-Neto
authors: Eduardo B
authors: EB
authors: Coelho
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000328:Adult; D001938:Brazil; D065095:Calcineurin Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D006084:Graft Rejection / Q000517:prevention & control*; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014018:Tissue Distribution
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D065095:Calcineurin Inhibitors; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus
keywords: ABCB1 diplotype; cytochrome P450; kidney transplantation; pharmacogenetics; tacrolimus pharmacokinetics