title: Influence of MRP2 on MPA pharmacokinetics in renal transplant recipients-results of the Pharmacogenomic Substudy within the Symphony Study.
abstract: BACKGROUND
  The aim of this study was to determine the relationship between single-nucleotide polymorphisms (SNPs) in MRP2 genes and mycophenolic acid (MPA) pharmacokinetics in renal transplant recipients of the Symphony Pharmacogenomic substudy.
  
  
  METHODS
  Sixty-six renal transplant recipients of eight Spanish centres were randomized into four branches of immunosuppressive regimen: low dose of cyclosporine, standard dose of cyclosporine, tacrolimus and sirolimus, all in addition to mycophenolate mofetil and steroids. Fifty-five patients were genotyped for SNPs in MRP2, C24T and C3972T. Pharmacokinetic sampling was done before MPA administration and up to 12 h post-dose at Day 7, 1 month and 3 months post-transplant. Relationships of area under the curve (AUC) of MPA and MPAG plasma sampling with the presence of MRP2 SNPs and with the immunosuppressive regimens were studied.
  
  
  RESULTS
  At steady-state conditions, MPA-reduced exposure was observed in C24T variant allele in MRP2 (CC: 68.73 ± 6.78; *T: 48.12 ± 4.90, P = 0.023); no significant differences linked to C3972T SNP were observed. Taking into account groups of treatment, lower MPA AUC in variant allele of C24T was only found under macrolides treatment with statistically significant differences at Month 3 (Tac and SRL, CC: 86.52 ± 10.98 versus *T: 41.99 ± 4.82, P = 0.001; CsA, CC: 52.31 ± 5.30 versus *T: 54.24 ± 8.30, P = 0.772); for C3972T, the same tendency was found but differences at steady state did not reach statistical significance.
  
  
  CONCLUSIONS
  Renal transplant recipients T carriers of C24T MRP2 with macrolides treatment were associated with reduced MPA AUC in steady-state conditions. Patients treated with cyclosporine lost the effect of this polymorphism.
authors.affiliation: Nephrology Service and Laboratory of Experimental Nephrology, Hospital Universitari de Bellvitge, Catalonia, Spain. nlloberas@ub.edu
authors.forename: Nuria
authors.initials: N
authors.lastname: Lloberas
authors.forename: Juan
authors.initials: J
authors.lastname: Torras
authors.forename: Josep Ma
authors.initials: JM
authors.lastname: Cruzado
authors.forename: Franc
authors.initials: F
authors.lastname: Andreu
authors.forename: Federico
authors.initials: F
authors.lastname: Oppenheimer
authors.forename: Jaime
authors.initials: J
authors.lastname: Sánchez-Plumed
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Gentil
authors.forename: Mercé
authors.initials: M
authors.lastname: Brunet
authors.forename: Henrik
authors.initials: H
authors.lastname: Ekberg
authors.forename: Josep M
authors.initials: JM
authors.lastname: Grinyó
mesh_terms: D019540:Area Under Curve; D016572:Cyclosporine / Q000627:therapeutic use; D004247:DNA / Q000235:genetics; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D005919:Glomerular Filtration Rate; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D007676:Kidney Failure, Chronic / Q000188:drug therapy* / Q000601:surgery; D007677:Kidney Function Tests; D016030:Kidney Transplantation; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000627:therapeutic use*; D010597:Pharmacogenetics; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D020123:Sirolimus / Q000627:therapeutic use; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D016559:Tacrolimus / Q000627:therapeutic use
chemical_list: D007166:Immunosuppressive Agents; C412617:KLHL1 protein, human; D008840:Microfilament Proteins; D016572:Cyclosporine; D004247:DNA; D009173:Mycophenolic Acid; D020123:Sirolimus; D016559:Tacrolimus