Increase in tacrolimus exposure after steroid tapering is influenced by CYP3A5 and pregnane X receptor genetic polymorphisms in renal transplant recipients

Frank Stifft*, Sander M. J. van Kuijk, Otto Bekers, Maarten H. L. Christiaans

*Corresponding author for this work

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Abstract

Background. Tacrolimus, a drug for prevention of rejection after kidney transplantation, has a narrow therapeutic window and is metabolized by the cytochrome P540 3A (CYP3A) system. Tacrolimus exposure increases after steroid tapering in many patients. The pregnane X receptor (PXR)-a mediator for CYP3A-has a steroid receptor and might regulate CYP3A5 activity depending on single nucleotide polymorphisms (SNPs) of CYP3A5 or PXR. This may contribute to differences in tacrolimus exposure after steroid tapering. Methods. In a cohort of renal transplant recipients, the influence of CYP3A5 and PXR SNPs (A7635G, C8055T and C25385T) on the dose-normalized Tacrolimus trough concentration (DnC(0)) and their potential interaction with each other after steroid taper were analysed by linear regression. Eligible were all 83 outpatient renal transplant patients on tacrolimus and steroids in a pharmacokinetic steady state at least 6 weeks after transplantation and whose blood was available for genetic analysis. Results. Compared with the CYP3A5*1/*3 genotype, the CYP3A5*3/*3 SNP showed a significantly stronger increase in DnC(0) after steroid taper (+0.29 mu g/L/mg; P = 0.002). Of the tested PXR SNPs, PXR G7635G individuals had a significantly stronger increase in DnC(0) (compared with A7635A, +0.31 mu g/L/mg; P = 0.02), with a weaker increase in A7635G heterozygotes (+0.17 mu g/L/mg; P = 0.124). There was neither interaction nor association between CYP3A5 and PXR SNPs. Conclusions. The magnitude of the DnC(0) increase due to steroid taper after renal transplantation is related to CYP3A5 SNPs. Independently, the PXR G7635G SNP is related to this increase, proving the role of PXR in tacrolimus metabolism.
Original languageEnglish
Pages (from-to)1668-1675
Number of pages9
JournalNephrology Dialysis Transplantation
Volume33
Issue number9
DOIs
Publication statusPublished - 1 Sep 2018

Keywords

  • pharmacokinetics
  • pharmacogenetics
  • pregnane X receptor (PXR)
  • tacrolimus
  • therapeutic drug monitoring
  • P-GLYCOPROTEIN
  • ORGAN-TRANSPLANTATION
  • HUMAN HEPATOCYTES
  • PHARMACOKINETICS
  • EXPRESSION
  • CORTICOSTEROIDS
  • DEXAMETHASONE
  • DISPOSITION
  • COMBINATION
  • METABOLISM

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