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The pregnane X receptor C-25385t single nucleotide polymorphism (SNP) does not affect tacrolimus pharmacokinetics in a large cohort of renal transplant recipients

H. de Jonge, M. Naesens, Y. Vanrenterghem, D. R. Kuypers

Ann Transplant 2008; 13(1): 33-33 :: ID: 880187

Abstract

Background: Tacrolimus is metabolized by CYP3A4/5 and is a substrate of p-glycoprotein (MDR1-gene). The pregnane X receptor (PXR) regulates the expression of these enzymes and drug-transporter and mediates their induction by steroids and other drugs. Recently, a significant impact of the PXRC-25385T SNP on tacrolimus apparent clearance was reported [1]. The aim of the current study was to investigate whether this SNP significantly affects tacrolimus pharmacokinetics in a large cohort of de novo renal transplant recipients.
Material/Methods: In a cohort of 93 renal allograft recipients tacrolimus exposure was measured by (12 and 4 h) concentration-time curves on day 7; 3, 6 months; 1, 2, 3, 4, and 5 years after transplantation. Patients were genotyped for the CYP3A5*1/*3, CYP3A4*1/*1b and PXR C-25385T SNP.
Results: There was no correlation between the PXR C-25385T SNP (CC 32%; CT 51%; TT 15%) and any of the studied tacrolimus pharmacokinetic parameters, including dose- and weight-normalised AUC[sub]0-12[/sub] and apparent clearance at any time point. Even when patients were stratifi ed according to CYP3A5 genotype (CYP3A5*1-carries: expressers vs CYP3A5*3/*3 homozygotes: non-expressers) no impact of the PXR C-25385T SNP was found in either of the two groups.
Conclusions: In this large cohort of renal transplant recipients we failed to confirm the recently reported lower apparent clearance and higher dose- and weight-normalised AUC[sub]0-12 [/sub]with an increasing number of T-alleles for the PXR C-25385T SNP, at any time-point up to 5 years after transplantation. Therefore it is unlikely that the PXR C-25385T polymorphism will be clinically relevant in renal transplantation.
References:
1. Benkali et al: Impact of NR1I2 (PXR) polymorphisms on tacrolimus pharmacokinetics in renal transplant patients. Am J Transplant, 2008; 8(Suppl.2): 633. (ATC Toronto, abstract 1711).

Keywords: Tacrolimus, Enzymes, transplant

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Annals of Transplantation eISSN: 2329-0358
Annals of Transplantation eISSN: 2329-0358