Impact of POR*28 on the pharmacokinetics of tacrolimus and cyclosporine A in renal transplant patients.
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.
*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.
Laure
L
Elens
Dennis A
DA
Hesselink
Rachida
R
Bouamar
Klemens
K
Budde
Johannes W
JW
de Fijter
Martine
M
De Meyer
Michel
M
Mourad
Dirk R J
DR
Kuypers
Vincent
V
Haufroid
Teun
T
van Gelder
Ron H N
RH
van Schaik
D000328:Adult; D000483:Alleles; D016572:Cyclosporine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D051799:Delayed Graft Function / Q000453:epidemiology; D004305:Dose-Response Relationship, Drug; D005500:Follow-Up Studies; D005838:Genotype; D006084:Graft Rejection / Q000453:epidemiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D016030:Kidney Transplantation; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D016559:Tacrolimus / Q000008:administration & dosage / Q000493:pharmacokinetics*
D007166:Immunosuppressive Agents; D016572:Cyclosporine; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009251:NADPH-Ferrihemoprotein Reductase; D016559:Tacrolimus