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01 December 2007

The CYP3A5*1/*3 single nucleotide polymorphism (SNP) determines the extent of drug interaction between tacrolimus and fluconazole in renal transplant recipients

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

Ann Transplant 2008; 13(1): 34-35 :: ID: 880191

Abstract

Background: Drug interactions between calcineurin-inhibitors and azole antifungals are characterized by a large clinical variability. The aim of this study was to examine the effect of CYP3A4, CYP3A5 and MDR1 SNPs on changes in tacrolimus trough concentrations and daily dose in renal transplant recipients treated with fluconazole.
Material/Methods: Out of 753 renal transplant recipients treated with tacrolimus, 29 patients were identified who received fluconazole treatment. These patients were genotyped for CYP3A4*1/*1B, CYP3A5*1/*3, MDR1 C3435T and G2677T/A and the effect of these SNPs on tacrolimus trough concentrations and dosing during fluconazole treatment was examined.
Results: Dose-corrected tacrolimus C0 did not increase significantly from baseline (1.26±1.23-fold) in heterozygous CYP3A5*1 carriers (n=6) during fluconazole therapy, as opposed to CYP3A5*3 homozygous patients (n=23) (3.28±2.34-fold; p=0.04 between CYP3A5*3/*3 and CYP3A5*3/*1 genotypes ). CYP3A5*3 homozygotes demonstrated a significant decrease in body weight-corrected tacrolimus dose during fluconazole administration (-54.7±23.7% from baseline, p<0.05) as opposed to heterozygous carriers of CYP3A5*1 (-25.1±29.9%; p=0.07 between CYP3A5*3/*3 and CYP3A5*3/*1 genotypes). These findings were not influenced by fluconazole dose or duration of treatment. More CYP3A5*3 homozygous patients were exposed to tacrolimus C0 ≥15 ng/mL during fluconazole therapy compared to CYP3A5*1 carriers (73.9% vs. 16.7%, p=0.01).
Conclusions: Renal transplant recipients with the CYP3A5*3/*3 genotype (non-expressers), are more susceptible for fluconazole-induced inhibition of tacrolimus metabolism as opposed to CYP3A5*1 carriers (expressers). Identification of this genetic determinant affecting the extent of this CYP3A-mediated drug interaction could potentially help to better manage drug interactions between tacrolimus and fluconazole.

Keywords: Tacrolimus, transplant, Broca

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