Laure Elens1, Dennis A Hesselink, Rachida Bouamar, Klemens Budde, Johannes W de Fijter, Martine De Meyer, Michel Mourad, Dirk R J Kuypers, Vincent Haufroid, Teun van Gelder, Ron H N van Schaik. 1. *Department of Clinical Chemistry, Erasmus University Medical Center, Rotterdam, the Netherlands; †Louvain Centre for Toxicology and Applied Pharmacology (LTAP) Department, Université catholique de Louvain, Brussels, Belgium; ‡Department of Internal Medicine and §Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, the Netherlands; ¶Department of Nephrology, Charite University, Berlin, Germany; ‖Department of Nephrology, Leiden University Medical Centre, Leiden, the Netherlands; **Surgery and Abdominal Transplantation Unit Cliniques universitaires St Luc, Université catholique de Louvain, Brussels, Belgium; and ††Department of Nephrology, University of Leuven, Leuven, Belgium.
Abstract
BACKGROUND: The P450 oxidoreductase (POR)*28 variant allele has been associated with altered cytochrome P450 3A enzyme activities. Both CYP3A5 and CYP3A4 are involved in the metabolism of calcineurin inhibitors and recent data show that POR*28 may explain part of the variability observed in tacrolimus (Tac) pharmacokinetics. The aim of this study was to investigate the impact of the POR*28 allele on Tac and cyclosporine A (CsA) immunosuppressive therapies. METHODS: Kidney transplant recipients receiving either Tac (n = 184) or CsA (n = 174), participating in a prospective multicenter trial, were genotyped for POR*28, CYP3A4*22, and CYP3A5*3. RESULTS: CYP3A5 expressers that were carriers of at least 1 POR*28 allele had a 16.9% decrease in dose-adjusted predose concentrations when compared CYP3A5 expressers that carried the POR*1/*1 genotype (P = 0.03), indicating an increased CYP3A5 activity for POR*28 carriers. In CYP3A5, nonexpressers carrying 2 POR*28 alleles, a 24.1% (confidence interval95% = -39.4% to -4.9%; P = 0.02) decrease in dose-adjusted predose concentrations was observed for Tac, suggesting higher CYP3A4 activity. For CsA, POR*28/*28 patients not expressing CYP3A5 and not carrying the CYP3A4*22 decrease-of-function allele showed 15% lower CsA dose-adjusted predose concentrations (P = 0.01), indicating also increased CYP3A4 activity. In both cohorts (ie, Tac and CsA), the POR*28 allele was neither associated with the incidence of delayed graft function nor with biopsy-proven acute rejection. These results were further confirmed in 2 independent cohorts. CONCLUSIONS: Our results show that the POR*28 allele is associated with increased in vivo CYP3A5 activity for Tac in CYP3A5 expressers, whereas POR*28 homozygosity was associated with a significant higher CYP3A4 activity in CYP3A5 nonexpressers for both Tac and CsA.
BACKGROUND: The P450 oxidoreductase (POR)*28 variant allele has been associated with altered cytochrome P450 3A enzyme activities. Both CYP3A5 and CYP3A4 are involved in the metabolism of calcineurin inhibitors and recent data show that POR*28 may explain part of the variability observed in tacrolimus (Tac) pharmacokinetics. The aim of this study was to investigate the impact of the POR*28 allele on Tac and cyclosporine A (CsA) immunosuppressive therapies. METHODS: Kidney transplant recipients receiving either Tac (n = 184) or CsA (n = 174), participating in a prospective multicenter trial, were genotyped for POR*28, CYP3A4*22, and CYP3A5*3. RESULTS:CYP3A5 expressers that were carriers of at least 1 POR*28 allele had a 16.9% decrease in dose-adjusted predose concentrations when compared CYP3A5 expressers that carried the POR*1/*1 genotype (P = 0.03), indicating an increased CYP3A5 activity for POR*28 carriers. In CYP3A5, nonexpressers carrying 2 POR*28 alleles, a 24.1% (confidence interval95% = -39.4% to -4.9%; P = 0.02) decrease in dose-adjusted predose concentrations was observed for Tac, suggesting higher CYP3A4 activity. For CsA, POR*28/*28 patients not expressing CYP3A5 and not carrying the CYP3A4*22 decrease-of-function allele showed 15% lower CsA dose-adjusted predose concentrations (P = 0.01), indicating also increased CYP3A4 activity. In both cohorts (ie, Tac and CsA), the POR*28 allele was neither associated with the incidence of delayed graft function nor with biopsy-proven acute rejection. These results were further confirmed in 2 independent cohorts. CONCLUSIONS: Our results show that the POR*28 allele is associated with increased in vivo CYP3A5 activity for Tac in CYP3A5 expressers, whereas POR*28 homozygosity was associated with a significant higher CYP3A4 activity in CYP3A5 nonexpressers for both Tac and CsA.
Authors: Laure Elens; Rachida Bouamar; Nauras Shuker; Dennis A Hesselink; Teun van Gelder; Ron H N van Schaik Journal: Br J Clin Pharmacol Date: 2014-04 Impact factor: 4.335
Authors: Rebecca A Pulk; David S Schladt; William S Oetting; Weihua Guan; Ajay K Israni; Arthur J Matas; Rory P Remmel; Pamala A Jacobson Journal: Pharmacogenomics Date: 2015-06-12 Impact factor: 2.533
Authors: G N Almeida-Paulo; I Dapía García; R Lubomirov; A M Borobia; N L Alonso-Sánchez; L Espinosa; A J Carcas-Sansuán Journal: Pharmacogenomics J Date: 2017-01-17 Impact factor: 3.550
Authors: W S Oetting; B Wu; D P Schladt; W Guan; R P Remmel; R B Mannon; A J Matas; A K Israni; P A Jacobson Journal: Pharmacogenomics J Date: 2017-11-21 Impact factor: 3.550
Authors: William S Oetting; Baolin Wu; David P Schladt; Weihua Guan; Rory P Remmel; Casey Dorr; Roslyn B Mannon; Arthur J Matas; Ajay K Israni; Pamala A Jacobson Journal: Pharmacogenomics Date: 2018-01-10 Impact factor: 2.533
Authors: Janaína B F Everton; Fernando J B Patrício; Manuel S Faria; Teresa C A Ferreira; Elen A Romao; Gyl E B Silva; Marcelo Magalhães Journal: Eur J Clin Pharmacol Date: 2021-01-05 Impact factor: 2.953
Authors: Dennis A Hesselink; Rachida Bouamar; Laure Elens; Ron H N van Schaik; Teun van Gelder Journal: Clin Pharmacokinet Date: 2014-02 Impact factor: 6.447