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Influence of MRP2 on MPA pharmacokinetics in renal transplant recipients-results of the Pharmacogenomic Substudy within the Symphony Study

Lloberas, Nuria; Torras, Juan; Ma Cruzado, Josep; Andreu, Franc; Oppenheimer, Federico; Sanchez-Plumed, Jaime; Angel Gentil, Miguel; Brunet, Merce; Ekberg, Henrik LU and Ma Grinyo, Josep (2011) In Nephrology Dialysis Transplantation 26(11). p.3784-3793
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... (More)
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 plasmasampling 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 (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Immunosuppressors, MRP2, mycophenolic acid, pharmacokinetics, single-nucleotide polymorphism
in
Nephrology Dialysis Transplantation
volume
26
issue
11
pages
3784 - 3793
publisher
Oxford University Press
external identifiers
  • wos:000296350400058
  • scopus:80155171939
ISSN
1460-2385
DOI
10.1093/ndt/gfr130
language
English
LU publication?
yes
id
e7081474-a630-43ed-9c26-a204634f368b (old id 2207741)
date added to LUP
2011-11-30 09:12:39
date last changed
2017-11-12 03:37:27
@article{e7081474-a630-43ed-9c26-a204634f368b,
  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 plasmasampling 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},
  author       = {Lloberas, Nuria and Torras, Juan and Ma Cruzado, Josep and Andreu, Franc and Oppenheimer, Federico and Sanchez-Plumed, Jaime and Angel Gentil, Miguel and Brunet, Merce and Ekberg, Henrik and Ma Grinyo, Josep},
  issn         = {1460-2385},
  keyword      = {Immunosuppressors,MRP2,mycophenolic acid,pharmacokinetics,single-nucleotide polymorphism},
  language     = {eng},
  number       = {11},
  pages        = {3784--3793},
  publisher    = {Oxford University Press},
  series       = {Nephrology Dialysis Transplantation},
  title        = {Influence of MRP2 on MPA pharmacokinetics in renal transplant recipients-results of the Pharmacogenomic Substudy within the Symphony Study},
  url          = {http://dx.doi.org/10.1093/ndt/gfr130},
  volume       = {26},
  year         = {2011},
}