The CYP3A5*1/*3 single nucleotide polymorphism (SNP) determines the extent of drug interaction between tacrolimus and ï¬‚uconazole in renal transplant recipients
H. de Jonge, M. Naesens, Y. Vanrenterghem, D. R. Kuypers
Ann Transplant 2008; 13(1): 34-35
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 ï¬‚uconazole.
Material/Methods: Out of 753 renal transplant recipients treated with tacrolimus, 29 patients were identified who received ï¬‚uconazole 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 ï¬‚uconazole 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 ï¬‚uconazole 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 ï¬‚uconazole 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 inï¬‚uenced by ï¬‚uconazole dose or duration of treatment. More CYP3A5*3 homozygous patients were exposed to tacrolimus C0 â‰¥15 ng/mL during ï¬‚uconazole 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 ï¬‚uconazole-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 ï¬‚uconazole.
Keywords: Tacrolimus, transplant, Broca