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Do drug transporter (ABCB1) SNPs and P-glycoprotein function influence cyclosporine and macrolides exposure in renal transplant patients? Results of the pharmacogenomic substudy within the symphony study

Llaudo, Ines ; Colom, Helena ; Gimenez-Bonafe, Pepita ; Torras, Joan ; Caldes, Anna ; Sarrias, Maria ; Cruzado, Josep Ma ; Oppenheimer, Federico ; Sanchez-Plumed, Jaime and Gentil, Miguel Angel , et al. (2013) In Transplant International 26(2). p.177-186
Abstract
The function of the efflux pump P-glycoprotein (Pgp) and ABCB1 single nucleotide polymorphisms (SNPs) should be considered as important tools to deepen knowledge of drug nephrotoxicity and disposition mechanisms. The aim of this study is to investigate the association of C3435T, G2677T, C1236T, and T129C ABCB1 SNPs with Pgp activity and exposure to different immunosuppressive drugs in renal transplant patients. Patients included in the Symphony Pharmacogenomic substudy were genotyped for ABCB1 SNPs. According to the design, patients were randomized into four immunosuppressive regimens: low and standard dose of cyclosporine (n = 30), tacrolimus (n = 13), and sirolimus (n = 23) concomitantly with mycophenolate and steroids. Pgp activity was... (More)
The function of the efflux pump P-glycoprotein (Pgp) and ABCB1 single nucleotide polymorphisms (SNPs) should be considered as important tools to deepen knowledge of drug nephrotoxicity and disposition mechanisms. The aim of this study is to investigate the association of C3435T, G2677T, C1236T, and T129C ABCB1 SNPs with Pgp activity and exposure to different immunosuppressive drugs in renal transplant patients. Patients included in the Symphony Pharmacogenomic substudy were genotyped for ABCB1 SNPs. According to the design, patients were randomized into four immunosuppressive regimens: low and standard dose of cyclosporine (n = 30), tacrolimus (n = 13), and sirolimus (n = 23) concomitantly with mycophenolate and steroids. Pgp activity was evaluated in PBMC using the Rhodamine 123 efflux assay. TT carrier patients on C3435T, G2677T, and C1236T SNPs (Pgp-low pumpers) showed lower Pgp activity than noncarriers. Pgp-high pumpers treated with cyclosporine showed lower values of Pgp function than macrolides. There was a negative correlation between cyclosporine AUC and Pgp activity at 3 months. Results did not show any correlation between tacrolimus and sirolimus AUC and Pgp activity at 3 months. We found an important role of the ABCB1 SNPs Pgp function in CD3+ peripheral blood lymphocytes from renal transplant recipients. Pgp activity was influenced by cyclosporine but not macrolides exposure. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ABCB1, cyclosporine, macrolides, polymorphisms, P-glycoprotein, transplantation
in
Transplant International
volume
26
issue
2
pages
177 - 186
publisher
Springer
external identifiers
  • wos:000313737600014
  • scopus:84872543515
  • pmid:23216707
ISSN
1432-2277
DOI
10.1111/tri.12018
language
English
LU publication?
yes
id
6d969a7d-6457-4106-91f7-6ac35ee0fde6 (old id 3589986)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/23216707
date added to LUP
2016-04-01 13:58:54
date last changed
2022-04-22 00:44:06
@article{6d969a7d-6457-4106-91f7-6ac35ee0fde6,
  abstract     = {{The function of the efflux pump P-glycoprotein (Pgp) and ABCB1 single nucleotide polymorphisms (SNPs) should be considered as important tools to deepen knowledge of drug nephrotoxicity and disposition mechanisms. The aim of this study is to investigate the association of C3435T, G2677T, C1236T, and T129C ABCB1 SNPs with Pgp activity and exposure to different immunosuppressive drugs in renal transplant patients. Patients included in the Symphony Pharmacogenomic substudy were genotyped for ABCB1 SNPs. According to the design, patients were randomized into four immunosuppressive regimens: low and standard dose of cyclosporine (n = 30), tacrolimus (n = 13), and sirolimus (n = 23) concomitantly with mycophenolate and steroids. Pgp activity was evaluated in PBMC using the Rhodamine 123 efflux assay. TT carrier patients on C3435T, G2677T, and C1236T SNPs (Pgp-low pumpers) showed lower Pgp activity than noncarriers. Pgp-high pumpers treated with cyclosporine showed lower values of Pgp function than macrolides. There was a negative correlation between cyclosporine AUC and Pgp activity at 3 months. Results did not show any correlation between tacrolimus and sirolimus AUC and Pgp activity at 3 months. We found an important role of the ABCB1 SNPs Pgp function in CD3+ peripheral blood lymphocytes from renal transplant recipients. Pgp activity was influenced by cyclosporine but not macrolides exposure.}},
  author       = {{Llaudo, Ines and Colom, Helena and Gimenez-Bonafe, Pepita and Torras, Joan and Caldes, Anna and Sarrias, Maria and Cruzado, Josep Ma and Oppenheimer, Federico and Sanchez-Plumed, Jaime and Gentil, Miguel Angel and Ekberg, Henrik and Grinyo, Josep Ma and Lloberas, Nuria}},
  issn         = {{1432-2277}},
  keywords     = {{ABCB1; cyclosporine; macrolides; polymorphisms; P-glycoprotein; transplantation}},
  language     = {{eng}},
  number       = {{2}},
  pages        = {{177--186}},
  publisher    = {{Springer}},
  series       = {{Transplant International}},
  title        = {{Do drug transporter (ABCB1) SNPs and P-glycoprotein function influence cyclosporine and macrolides exposure in renal transplant patients? Results of the pharmacogenomic substudy within the symphony study}},
  url          = {{http://dx.doi.org/10.1111/tri.12018}},
  doi          = {{10.1111/tri.12018}},
  volume       = {{26}},
  year         = {{2013}},
}