title: Influence of the CYP3A4/5 genetic score and ABCB1 polymorphisms on tacrolimus exposure and renal function in Brazilian kidney transplant patients.
abstract: Polymorphisms in genes encoding transport proteins and metabolizing enzymes involved in tacrolimus (TAC) disposition may be important sources of individual variability during treatment.
  
  
  
  The aim of this study was to investigate the effect of combined CYP3A4 and CYP3A5 variants, using a CYP3A4/5 genetic score, and ABCB1 polymorphisms on therapeutic TAC monitoring and their relationship with clinical outcomes.
  
  
  
  Brazilian kidney transplant recipients (n=151), who received TAC over 3 months after transplantation, were genotyped for CYP3A4 rs2242480 (g.20230G>A), CYP3A5 rs15524 (g.31611C>T) and rs776746 (g.6986A>G), ABCB1 rs1128503 (c.1236C>T), rs1045642 (c.3435C>T), and rs2032582 (c.2677G>T/A) polymorphisms.
  
  
  
  Frequencies of CYP3A4 g.20230A, CYP3A5 g.31611C, and g.6986A were 0.37, 0.26, and 0.28, respectively. These alleles were associated with TAC rapid metabolization and were used for CYP3A4/5 genetic score construction. A higher CYP3A4/5 genetic score was associated with higher TAC dose and lower concentrations for dose administered (Co/D, P<0.05). Ninety days after transplantation, the presence of two or more rapid metabolization alleles contributed toward 27.7% of Co/D variability and was associated with a lower estimated glomerular filtration rate values (P<0.05). For ABCB1, the frequencies of c.1236T, c.3435T, and c.2677T/A alleles were 0.42, 0.42, and 0.33/0.04. At 30 days after transplantation, patients carrying ABCB1 c.1236TT+c.3435TT+(c.2677TT+TA) genotypes had higher TAC Co/D than those with common or heterozygous genotypes (P<0.05).
  
  
  
  The results show the impact of the CYP3A4/5 genetic score on TAC exposure and renal function in Brazilian patients. Furthermore, ABCB1 polymorphisms, in a combined analysis, influenced TAC Co/D at 30 days after transplantation.
authors.affiliation: aDepartment of Clinical and Toxicological Analysis, School of Pharmaceutical Sciences bDepartment of Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo cNephrology Division, Hospital do Rim, Universidade Federal de São Paulo, Sao Paulo, Brazil dCenter of Molecular Biology and Pharmacogenetics, BIOREN-CEGIN, Universidad de La Frontera, Temuco, Chile eSchool of Medicine, Uniformed Services University, Bethesda, Maryland, USA.
authors.forename: Fabiana D V
authors.initials: FD
authors.lastname: Genvigir
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Salgado
authors.forename: Claudia R
authors.initials: CR
authors.lastname: Felipe
authors.forename: Elena Y F
authors.initials: EY
authors.lastname: Luo
authors.forename: Camila
authors.initials: C
authors.lastname: Alves
authors.forename: Alvaro
authors.initials: A
authors.lastname: Cerda
authors.forename: Helio
authors.initials: H
authors.lastname: Tedesco-Silva
authors.forename: Jose O
authors.initials: JO
authors.lastname: Medina-Pestana
authors.forename: Nagilla
authors.initials: N
authors.lastname: Oliveira
authors.forename: Alice C
authors.initials: AC
authors.lastname: Rodrigues
authors.forename: Sonia Q
authors.initials: SQ
authors.lastname: Doi
authors.forename: Mario H
authors.initials: MH
authors.lastname: Hirata
authors.forename: Rosario D C
authors.initials: RD
authors.lastname: Hirata
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D001938:Brazil; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D000071184:Pharmacogenomic Variants; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus